Small Injection Volumes Research Articles

QUALITY ASSURANCE OF SMALL VOLUME PARENTERAL PRODUCT WITH QUALITY BY DESIGN APPROACH: A REVIEW

Background: Nowadays, many small-volume injection products are circulating on the market. Small-volume parenteral (SVP) products are usually designed for treatment purposes that provide systemic effects. If it is not produced strictly, the product will be hazardous and even life-threatening. Quality assurance is one of the primary tools used to ensure the acceptable performance of SVP products. Quality by design (QbD) represents a systematic strategy for product development that starts with setting a target product quality and emphasizes product process control based on a scientific approach and quality risk assessment. The purpose is to ensure SVP product quality from design to production process. Objective: This review will determine generally Critical Quality Attributes (CQA), Critical Material Attributes (CMA), and Critical Process Parameters (CPP) in terms of explaining the quality assurance of SVP products with a quality-by-design approach. Methods: All articles were obtained by electronic search using ICH guidelines, Science Direct, and Google Scholar. Results: From the literature review, it was found that using a quality-by-design approach through integrated CQA, CMA, and CPP can produce SVP products that comply with QTPP (Quality Target Product Profile) and regulatory requirements. Conclusion: QbD has been established as a valuable scientific approach for ensuring quality assurance within the pharmaceutical industry. Pharmaceutical companies prioritize obtaining regulatory approval before introducing any product to the market. Keywords: Critical Process Parameter; Critical Quality Attributes; Quality by Design; Parenteral; Small Volume Parenteral.

The Physiological Responses to Stellate Ganglion Blockade under Ultrasound-Guidance in the Rat

The stellate ganglion (SG) is an essential component of the sympathetic nervous system, where inhibition via local anesthetics is used as a practical approach to manage many clinical disorders, including regional pain syndrome and cardiovascular diseases. However, this procedure is often technically challenging, with side effects including pneumothorax and vascular injection. Ultrasound-guided SG blockade (SGB) is currently adopted as a more effective method than blind injection techniques as it allows for visualizing SG’s location. However, there is not yet enough information on the physiological responses of this procedure. The present study examined physiological changes following ultrasound-guided SGB in normal rats. We hypothesized that ultrasound-guided SGB is a safe and effective method to inhibit sympathetic nerves in the rat. Male Sprague-Dawley rats (310-350 g) were anesthetized with 2-4% isoflurane and placed on the animal monitor platform (VisualSonics Vevo, SR200) that allowed for monitoring and recording the electrocardiogram, respiratory rate, and body temperature. Normal saline (0.9%) or 1.0-1.5% lidocaine mixed with Chicago blue dye was loaded in a 1 ml insulin syringe with a 26 G needle. Each tested solution in 40-60 μl was injected into the right or left SG region once under ultrasound guidance (VisualSonics Vevo 3100 LT). Ten minutes after the injection, rats were allowed to recover from the anesthesia, and the status of the eyelid and the general condition were examined. Ptosis was observed on the ipsilateral side as the lidocaine was administered to the right (n=9) or left (n=7) sides of SG, indicating the successful execution of SGB. No ptosis was noted in any controls as normal saline was injected into the right (n=6) or left (n=6) SG. Respiratory rate and body temperature were unchanged following the injection in either the right or left side in any control or treatment groups. Heart rate (HR) was significantly decreased after administering lidocaine (354 ± 14 vs. 292 ± 16 bpm, P = 0.008; pre- vs. after-injection) but not normal saline into right SG. Reduced HR lasted for about 7-10 minutes. HR was unaltered after injecting lidocaine or normal saline into the left SG. These data imply that sympathetic nerves controlling HR are likely predominantly associated with right SG. Besides, no abnormal behaviors were noted in any rat. Chicago blue dye was confirmed to be distributed in the SG region. No bleeding and tissue damage were evident in the injected SG area. The results suggest that non-invasive ultrasound-guided SGB is likely a safe and effective approach with a small injection volume to block sympathetic nerves in the rat, which sheds light on its employment in experimental research and clinical practice. Research fund from AEON Biopharma, Inc. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

E057 International survey to evaluate current options and user needs for subcutaneous injection of methotrexate to inform development of a new injection device

Abstract Background/Aims Prefilled syringes (PFS) and various types of pens are available for subcutaneous injection of methotrexate (MTX) in patients with rheumatoid arthritis or moderate to severe psoriasis. To assess the needs of users and the relevance of features of a new MTX autoinjector succeeding the metoject®/metex® PEN, an international online survey was performed. Methods A structured questionnaire was distributed to physicians, nurses and patients in Germany, France, and the United Kingdom. Participants received illustrations of the three MTX devices currently available on the market and were informed about the new MTX autoinjector. Results In total, 189 rheumatologists, 111 dermatologists, 90 nurses, and 180 patients answered the questions. Specific reasons for a preference for the use of MTX pens over PFS could predominantly be assigned to the categories “dosing/administration” and “ease of use”. 82% of physicians, 87% of nurses, and 76% of patients stated a positive first impression of the new button-free MTX autoinjector, respectively. The features rated most relevant by the user groups were a) 2-step autoinjector mechanism (receiving a mean 14.1 to 18.1 points of a total of 100 points), b) small injection volume (9.7 to 11.7 points), c) short injection time below 5 seconds (8.5 to 11.1 points), and d) 10 different doses for dose flexibility (8.0 to 13.2 points). Conclusion Autoinjectors for MTX appear to be preferred over PFS in this international survey. In addition, important features of MTX autoinjectors for patients and healthcare professionals were identified including the autoinjector mechanism, volume of injection and injection time. Disclosure U. Müller-Ladner: Consultancies; U.M.-L. was advisor to medac GmbH. Member of speakers’ bureau; U.M.-L. was speaker to medac GmbH. C. Edwards: Member of speakers’ bureau; C.J.E. has been a speaker for medac. A. Erkens: Other; A.E. has performed strategic market research for medac GmbH.

Relevance of Adalimumab Product Attributes to Patient Experience in the Biosimilar Era: A Narrative Review.

Adalimumab (ADL, Humira®, reference product), an anti-TNF-α biologic, has transformed the treatment of chronic, immune-mediated inflammatory diseases. However, the high cost of ADL therapy has driven the development of more affordable ADL biosimilars, agents with no clinically meaningful differences from the reference product. This review summarizes the product attributes of reference ADL and the nine ADL biosimilars approved and available in the USA in relation to patient experience of injection-site pain (ISP). Product formulation, delivery volume and device features (e.g., type and needle gauge size) influence patient experience of ISP with potential clinical consequences. Citrate-free formulations generally cause less ISP; injection volumes of > 1.5ml may be associated with increased ISP. Reference ADL and all ADL biosimilars offer a citrate-free formulation, and reference ADL and four ADL biosimilars offer a high-concentration solution that allows a smaller injection volume. All available ADL products are injected subcutaneously using either a pre-filled pen (PFP) or pre-filled syringe (PFS). Patients prefer the PFP, but the PFS permits better control over the speed and duration of injection. Smaller (29-gauge) needle outer diameter is associated with less ISP; reference ADL and seven ADL biosimilars offer a device with a 29-gauge needle. In the USA, an approved biosimilar can be designated "interchangeable," allowing pharmacy-level substitution, where state law permits. In the USA, two ADL biosimilars have received interchangeability designation; others are seeking interchangeability designation from the Food and Drug Administration (n = 2), are being evaluated in clinical studies to support interchangeability (n = 2), or do not have/are not seeking interchangeability designation (n = 3). Product-related attributes influence patient experience of ISP caused by subcutaneous ADL injection. Reference ADL and ADL biosimilar products differ in their attributes, so discussion with patients about treatment options is essential to optimize adherence and outcomes.

International Survey to Evaluate Current Options for Subcutaneous Injection of Methotrexate (MTX) and a New Button-Free MTX Autoinjector.

Prefilled syringes (PFS) and various types of pens are available for subcutaneous injection of methotrexate (MTX) in patients with rheumatoid arthritis or moderate to severe psoriasis. A new MTX pen with modernized button-free autoinjection technology was developed as a successor to a button-activated pen (metoject®/metex®PEN). To assess the needs of users and the relevance of features of the new MTX autoinjector an international online survey was performed. A structured questionnaire was distributed to physicians, nurses and patients in Germany, France, and the United Kingdom. Participants received illustrations and information about features of the new MTX autoinjector. In total, 189 rheumatologists, 111 dermatologists, 90 nurses, and 180 patients answered the questions. Specific reasons for a preference for the use of MTX pens over PFS could predominantly be assigned to the categories "dosing/administration" and "ease of use". The first impression of the new MTX autoinjector was positive in 82% of physicians, 87% of nurses, and 76% of patients, respectively. The four most important features of the new MTX autoinjector were 2-step autoinjector mechanism (receiving a mean 14.1 to 18.1 chips of a total of 100 chips), small injection volume (9.7 to 11.7 chips), 10different doses for dose flexibility (8.0 to 13.2 chips), and short injection time below 5seconds (8.5 to 11.1 chips). Arguments for the use of MTX pens as opposed to PFS predominantly refer to dosing/administration and ease of use. The new button-free MTX autoinjector combines a number of advantageous features identified by the international survey.

Research on combustion process optimization of marine diesel engines based on dual-injector system

Marine diesel engines are widely used with their strong power and mature technology. However, in recent years, the emphasis on environmental protection has made combustion pollutants the focus of attention, and the new regulations of the International Maritime Organization (IMO) and various countries have put forward new requirements and challenges for diesel engine combustion and emission performance. Due to the large size and large amount of circulating fuel injection, the incomplete mixing of fuel in the cylinder and the local violent combustion of high-power medium-speed marine diesel engines are important reasons for low thermal efficiency and high pollutant emissions. To achieve efficient and clean combustion of fuel in the cylinder, a dual-injector combustion system is designed on a dual-fuel engine basis, aiming to add a micro-injection before the central injection and provide positive in-cylinder flow and hot atmosphere for the atomized combustion of the central-injection fuel, so that the combustion in the cylinder is reasonably arranged, the thermal efficiency is improved and NOx emissions are reduced. The 3D simulation model was established by CFD software CONVERGE, and the physical model was calibrated according to the data of the pure diesel mode of the dual-fuel engine, and the influence of the small pilot-injection fuel volume on the development of spray and combustion in the cylinder at high and low load was analyzed. It was found that the small pilot-injection fuel volume at a high load had little effect on the atomization evaporation of the main-injection fuel and the hot atmosphere in the cylinder, so the improvement effect of combustion quality was not obvious, while the pilot-injection volume with the same pilot-injection capacity as high load relatively accounted for a large proportion at the low load with a small cycle injection volume. Without changing the injector specification settings of the original dual-fuel engine, the thermal efficiency was increased by 6.13% and the NOx generation was reduced by 22.42% by optimizing the injection timing, injection duration, and injection amount.

Refinement of intrathecal catheter design to enhance neuraxial distribution

BackgroundDelivery of therapeutics via indwelling intrathecal catheters is highly efficacious for targeting of pain, spasticity, neuraxial cancer and neurodegenerative disorders. However, current catheter designs have some major limitations. Given limited CSF flow, fixed intrathecal volume and the large distance of the rostro-caudal spinal axis, current intrathecal delivery routes fail to achieve adequate drug distribution. Additionally open catheter systems are plagued with cellular ingrowth and debris accumulation if used intermittently. New method1.We addressed these issues by designing a new catheter that includes micro-valves2.Micro-valves distributed along the catheter open simultaneously upon adequate local transmural pressure, which is evenly distributed along the catheter fluid column.3.Buildup of transmural pressure, prior to microvalve opening, results in increased solute exit velocity.4.Micro-valves are closed when not in use, preventing anything from entering the system, and allowing for long-term intermittent use. Results/comparison with existing method(s)High speed imaging showed micro-valve catheters greatly increase fluid exit velocities compared to typical open-ended catheters, which prevents pooling of injectate proximal to the opening. When implanted intrathecally in rats, small injection volumes (7.5 μL) of dye or AAV9-RFP, resulted in an even rostro-caudal distribution along the spinal axis and robust transfection of neurons from cervical to lumbar dorsal root ganglia. In contrast, such injections with an open-ended catheter resulted in localized distribution and transfection proximal to the delivery site.Our poly micro-valve catheter design resulted in equivalent transfection rates of cervical DRG neurons using 100x lower titer of AAV9-RFP. Unlike open port catheters, no debris accumulation was observed in the lumen of implanted catheters, showing potential for long-term intermittent use. ConclusionsThis catheter platform, suitable for small animal models is easily scalable for human use and addresses many of the problems observed with common catheter systems.

Simultaneous determination of tramadol and paracetamol in human plasma using LC-MS/MS and application in bioequivalence study of ­fixed-dose combination

The study aimed to develop a sensitive and high-throughput liquid chromatography coupled with tandem mass spectrometry method to quantify concentrations of tramadol and paracetamol simultaneously in human plasma. Sample preparation involved single-step protein precipitation using methanol and two deuterated internal standards, tramadol D6 and paracetamol D4. Agilent Poroshell 120 EC-C18 (100 × 2.1 mm, 2.1 µm) analytical column was employed to achieve chromatographic separation. Detection was in positive ion multiple reaction monitoring mode. A tailing factor (Tf) of <1.2, separation factor (K prime) of >1.5 from the column dead time and signal-to-noise (S/N) ratio >10, were obtained for analytes and internal standards. The standard curve was linear over the concentration range of 2.5–500.00 ng/mL for tramadol and 0.025–20.00 μg/mL for paracetamol. A small injection volume of 1 µL, low flow rate of 440 µL/min and short analysis time of 3.5 min reduced the solvent consumption, analysis cost and system contamination. The results of method validation parameters fulfilled the acceptance criteria of bioanalytical guidelines. The method was successfully applied to a bioequivalence study of fixed-dose combination products of tramadol and paracetamol in Malaysian healthy subjects.

Mechanosensitive enteric neurons in the guinea pig gastric fundus and antrum.

Coping with the ingested food, the gastric regions of fundus, corpus, and antrum display different motility patterns. Intrinsic components of such patterns involving mechanosensitive enteric neurons (MEN) have been described in the guinea pig gastric corpus but are poorly understood in the fundus and antrum. To elucidate mechanosensitive properties of myenteric neurons in the gastric fundus and antrum, membrane potential imaging using Di-8-ANEPPS was applied. A small-volume injection led to neuronal compression. We analyzed the number of MEN and their firing frequency in addition to the involvement of selected mechanoreceptors. To characterize the neurochemical phenotype of MEN, we performed immunohistochemistry. In the gastric fundus, 16% of the neurons reproducibly responded to mechanical stimulation and thus were MEN. Of those, 83% were cholinergic and 19% nitrergic. In the antrum, 6% of the neurons responded to the compression stimulus, equally distributed among cholinergic and nitrergic MEN. Defunctionalizing the sensory extrinsic afferents led to a significant drop in the number of MEN in both regions. We provided evidence for MEN in the gastric fundus and antrum and further investigated mechanoreceptors. However, the proportions of the chemical phenotypes of the MEN differed significantly between both regions. Further investigations of synaptic connections of MEN are crucial to understand the hardwired neuronal circuits in the stomach.

Real-time detection of isoprene marker gas based on micro-integrated chromatography system with GOQDs-modified μGC column and metal oxide gas detector

Isoprene is a typical physiological marker that can be used to screen for chronic liver disease. This work developed a portable micro-integrated chromatography analysis system based on micro-electromechanical system technology, nanomaterials technology and embedded microcontroller technology. The system integrated components such as graphene oxide quantum dots modified semi-packed microcolumn, In2O3 nanoflower (NF) gas-sensitive detector and 3D printed miniature solenoid valve group. The effectiveness of the separation effect of the micro-integrated system was verified by gas mixture test; the laws of the influence of carrier gas pressure and column temperature on the chromatographic separation performance, respectively, were investigated, and the working conditions (column temperature 90 °C and carrier gas pressure 7.5 kPa) for system testing were determined. The percentages of relative standard deviation of the peak areas and retention times obtained for the separated gases were in the range of 0.95%–6.06%, indicating the good reproducibility of the system. Meanwhile, the microintegrated system could detect isoprene down to 50 ppb at small injection volume (1 ml). The system response increased with increasing isoprene concentration and was linearly correlated with isoprene concentration (R 2 = 0.986), indicating that the system was expected to be used for trace detection of isoprene, a marker gas for liver disease, in the future.

Conceptualisation of a novel electromechanical system for small-volume needle-free jet injection

Needle-free jet injectors are minimally invasive drug delivery systems that utilise high-velocity microjets (∼100 m/s) created by pressurising the liquid drug through a micronozzle (50–300 µm in diameter). Most of the current commercially available jet injectors use a mechanical power possessed by a compressed spring or air to pressurise the fluid inside the injection chamber to deliver the liquid drug (typically ∼100 µL in volume) into the skin matrix. However, they cannot be utilised for achieving shallow penetration depths as they lack dynamic control that can shape the real-time microjet characteristics. Recently, electrically or optically powered jet injection systems are being developed to achieve shallow penetration depth by small-volume (<5 μL) injections. However, they require complex system and have a limited injection frequency (maximum reported value is 16 Hz). Herein, we propose a novel electro-mechanical jet injection system, where a mechanically actuated source pressurises the fluid inside the injection chamber and an electrically actuated system controls the characteristics of the propelled microjet. A computational model was developed to prove the feasibility of the proposed system, and the obtained results showed that the proposed system could produce stable small-volume microjets at about 100 Hz frequency that could be utilised for drug delivery applications.

Portable smartphone‐based microfluidic electrochemical immunosensor for ultrasensitive detection of alpha‐fetoprotein in human serum

AbstractRapid and accurate tracing of biomarkers is essential for early detecting and diagnosing of cancer. Therefore, a valid and convenient strategy needs to be developed for efficient monitoring of cancer biomarkers. Herein, we constructed a portable microfluidic electrochemical immunosensor based on three‐dimensional reduced graphene oxide (3D rGO) doped with gold nanoparticles (Au NPs) for ultrasensitive determination of alpha‐fetoprotein (AFP). The designed microfluidic chip, with the advantages of small injection volume, detachable structure and high integration, was fabricated by 3D printing, which only needed 9 μL of reagent to realize the high sensitivity detection. In addition, the 3D Au NPs‐rGO composites with high specific surface area and electrons transfer capacity can effectively increase electroactive sites and enhance electrochemical signals. Benefiting from these features, the 3D Au NPs‐rGO microfluidic electrochemical immunochip showed a wide detection range between 0.1 pg/mL–200 ng/mL and a best detection limit of 0.045 pg/mL with the high sensitivity of 175.008 μA (ng/mL)−1 cm−2. Meanwhile, the proposed immunosensor exhibited reliable AFP detection in human serum samples, which demonstrated that this portable smartphone‐based microfluidic electrochemical immunosensor hold great promises in clinical detection and huge potential in personalized healthcare.

Modeling hydrodynamic regime of the technogenic aquifer within the Noyabrsky site of the Aikhal mine

The Noyabrsky site is used for the injection of highly mineralized drainage waters formed during the development of the Aikhal kimberlite pipe (Republic of Sakha (Yakutia), Russia). The water injected into the wells of the site since 2013 has formed a localized intrapermafrost technogenic aquifer. Taking into account the porosity parameters of the formed permafrost reservoirs, as well as the confirmed useful capacity of the site, its operation is planned to continue until 2044 at the very least. Despite relatively small injection volumes (up to 430 m3/day), forecasting dynamical changes in the hydrodynamic regime of the technogenic water horizon is a challenging task, which is of significant practical importance for the provision of environmental and industrial safety. The assessment of the anthropogenic impact, as well as the subsequent forecasting of the hydrodynamic regime dynamics within the Noyabrsky site, were carried out by modeling methods in the Modflow software. The brine lens formed today is characterized by uneven porosity parameters, which is due to the peculiarities of heat and mass transfer when using permafrost for drainage water injection. Based on the results of predictive modeling a conclusion can be derived that the use of the method of Aikhal mine drainage water injection into the permafrost strata at the Noyabrsky site allows to reduce the influence degree of mining and production operations on the geological environment of the studied area through its localization on an intentionally limited, relatively small area, where injection is carried out, as well as on the environment, by preventing drainage brines from entering surface waters until 2044.

Microneedles Facilitate Small-Volume Intracochlear Delivery Without Physiologic Injury in Guinea Pigs.

Microneedle-mediated intracochlear injection through the round window membrane (RWM) will facilitate intracochlear delivery, not affect hearing, and allow for full reconstitution of the RWM within 48 hours. We have developed polymeric microneedles that allow for in vivo perforation of the guinea pig RWM and aspiration of perilymph for diagnostic analysis, with full reconstitution of the RWM within 48 to 72 hours. In this study, we investigate the ability of microneedles to deliver precise volumes of therapeutics into the cochlea and assess the subsequent consequences on hearing. Volumes of 1.0, 2.5, or 5.0 μL of artificial perilymph were injected into the cochlea at a rate of 1 μL/min. Compound action potential (CAP) and distortion product otoacoustic emission were performed to assess for hearing loss (HL), and confocal microscopy was used to evaluate the RWM for residual scarring or inflammation. To evaluate the distribution of agents within the cochlea after microneedle-mediated injection, 1.0 μL of FM 1-43 FX was injected into the cochlea, followed by whole mount cochlear dissection and confocal microscopy. Direct intracochlear injection of 1.0 μL of artificial perilymph in vivo , corresponding to about 20% of the scala tympani volume, was safe and did not result in HL. However, injection of 2.5 or 5.0 μL of artificial perilymph into the cochlea produced statistically significant high-frequency HL persisting 48 hours postperforation. Assessment of RWMs 48 hours after perforation revealed no inflammatory changes or residual scarring. FM 1-43 FX injection resulted in distribution of the agent predominantly in the basal and middle turns. Microneedle-mediated intracochlear delivery of small volumes relative to the volume of the scala tympani is feasible, safe, and does not cause HL in guinea pigs; however, injection of large volumes induces high-frequency HL. Injection of small volumes of a fluorescent agent across the RWM resulted in significant distribution within the basal turn, less distribution in the middle turn, and almost none in the apical turn. Microneedle-mediated intracochlear injection, along with our previously developed intracochlear aspiration, opens the pathway for precision inner ear medicine.

Crystalline Antibody-Laden Alginate Particles: A Platform for Enabling High Concentration Subcutaneous Delivery of Antibodies.

Subcutaneous (SC) administration is a desired route for monoclonal antibodies (mAbs). However, formulating mAbs for small injection volumes at high concentrations with suitable stability and injectability is a significant challenge. Here, this work presents a platform technology that combines the stability of crystalline antibodies with injectability and tunability of soft hydrogel particles. Composite alginate hydrogel particles are generated via a gentle centrifugal encapsulation process which avoids use of chemical reactions or an external organic phase. Crystalline suspension of anti-programmed cell death protein1 (PD-1) antibody (pembrolizumab) is utilized as a model therapeutic antibody. Crystalline forms of the mAb encapsuled in the hydrogel particles lead to stable, high concentration, and injectable formulations. Formulation concentrations as high as 315mg mL-1 antibody are achieved with encapsulation efficiencies in the range of 89-97%, with no perceivable increase in the number of antibody aggregates. Bioanalytical studies confirm superior maintained quality of the antibody in comparison with formulation approaches involving organic phases and chemical reactions. This work illustrates tuning the alginate particles' disintegration by using partially oxide alginates. Crystalline mAb-laden particles are evaluated for their biocompatibility using cell-based in vitro assays. Furthermore, the pharmacokinetics (PK) of the subcutaneously delivered human anti-PD-1 mAb in crystalline antibody-laden alginate hydrogel particles in Wistar rats is evaluated.

Evaluation of Anesthetic and Cardiorespiratory Effects after Intramuscular Administration of Three Different Doses of Telazol® in Common Marmosets (Callithrix jacchus).

Marmosets' small body size makes anesthesia challenging. Ideally, small volumes of drugs should be administered intramuscularly (i.m.). In addition, dose-dependent sedation and anesthesia are desirable properties for sedatives and anesthetics in marmosets. Telazol® (tiletamine and zolazepam) is highly concentrated, allowing the use of small injection volumes and dose-dependent sedation and anesthesia. A randomized, blinded study with crossover design in ten healthy adult common marmosets (Callithrix jacchus) was performed to evaluate the anesthetic and cardiorespiratory effects of three doses of i.m. Telazol® (respectively, 5, 10, and 15 mg/kg). Depth of anesthesia, cardiorespiratory effects, and induction, immobilization, and recovery times were determined. A significant difference was observed in immobilization time between 5 and 15 mg/kg of Telazol®. In addition, 15 mg/kg of Telazol® resulted in increased recovery times compared to 5 mg/kg. The cardiorespiratory effects during the first 45 min of immobilization were within clinically acceptable limits. The pedal withdrawal reflex was the best indicator of the anesthetic depth.

Efficacy and safety of pneumatic vitreolysis for management of vitreomacular traction syndrome

AbstractPurpose: To evaluate the outcome of small volume injection of perfluoropropane (C3F8) gas for symptomatic vitreomacular traction (VMT).Methods: A retrospective review of eyes with VMT treated with a limited volume of 0.2 ml of C3F8 gas was performed with limited face‐down position. Main outcome measures were release of VMT, best‐corrected visual acuity (BCVA), central macular thickness (CMT) and adverse events.Results: Ten consecutive patients with symptomatic VMT underwent pneumatic vitreolysis. Overall success was of 90% in VMT release. The CMT decreased from 397,8 μm ±) 81.87) preoperatively to 309,8 μm ±) 51.76) postoperatively (p &lt; 0.001). Mean BCVA improved from 0.42 ±) 0.24) to 0.24±) 0.23) logMAR at 6 months (p &lt; 0.001). One patient with a large VMT had no change in the optical coherence tomography aspect. Another patient with large VMT associated to large retrofoveal cyst has VMT release but formed a macular hole after gas injection. No other adverse events were seen.Conclusions: Pneumatic vitreolysis with small volume of C3F8 and limited face‐down position is a viable option for treating VMT with few adverse events. Macular hole formation can occur in cases of large retrofoveal cysts.

Recent Advances in Single-Cell Metabolomics Based on Mass Spectrometry

Recent Advances in Single-Cell Metabolomics Based on Mass Spectrometry

Simple and high sample throughput LC/ESI-MS/MS method for bioequivalence study of prazosin, a drug with risk of orthostatic hypotension

Objective The study aimed to develop a rapid, simple and sensitive LC/ESI-MS/MS method to measure prazosin concentration in human plasma and apply bedside sampling in bioequivalence study of two prazosin tablets to resolve the adverse effect of orthostatic hypotension. Significance The LC/ESI-MS/MS prazosin method was highly sensitive and selective. Bedside sampling reduced the orthostatic hypotension incidence and subject dropout rate. Methods After sample preparation, prazosin and terazosin (IS) were detected on mass spectrometer operating in multiple reaction monitoring mode using positive ionization. Mobile phase flow rate was set at 0.40 mL/min with sample run time of 1.75 min. The bioanalytical method was validated as per EMEA and FDA guidelines. Bedside sampling was performed in bioequivalence study for the first 4 h after dosing. The three primary pharmacokinetic parameters, C max, AUC0- t and AUC0-∞ and 90% confidence interval were determined. Results The small injection volume of 1 μL minimized instrumentation contamination and prolonged the analytical column lifespan. Linearity was obtained between 0.5 and 30.0 ng/mL, with coefficient of determination, r 2 ≥ 0.99. The mean extraction recovery of prazosin and IS was >92%, with precision value (CV, %) ≤ 10.3%. Only two orthostatic hypotension adverse events were reported. The two prazosin formulations were found to be bioequivalent. Conclusion The LC/ESI-MS/MS method has shown robustness and reliability exemplified by the incurred sample re-analysis result. Bedside sampling should be proposed for bioequivalence or pharmacokinetic studies of drugs demonstrating adverse event of orthostatic hypotension.

Insights for crystal mush storage utilizing mafic enclaves from the 2011–12 Cordón Caulle eruption

Two distinct types of rare crystal-rich mafic enclaves have been identified in the rhyolite lava flow from the 2011–12 Cordón Caulle eruption (Southern Andean Volcanic Zone, SVZ). The majority of mafic enclaves are coarsely crystalline with interlocking olivine-clinopyroxene-plagioclase textures and irregular shaped vesicles filling the crystal framework. These enclaves are interpreted as pieces of crystal-rich magma mush underlying a crystal-poor rhyolitic magma body that has fed recent silicic eruptions at Cordón Caulle. A second type of porphyritic enclaves, with restricted mineral chemistry and spherical vesicles, represents small-volume injections into the rhyolite magma. Both types of enclaves are basaltic end-members (up to 9.3 wt% MgO and 50–53 wt% SiO2) in comparison to enclaves erupted globally. The Cordón Caulle enclaves also have one of the largest compositional gaps on record between the basaltic enclaves and the rhyolite host at 17 wt% SiO2. Interstitial melt in the coarsely-crystalline enclaves is compositionally identical to their rhyolitic host, suggesting that the crystal-poor rhyolite magma was derived directly from the underlying basaltic magma mush through efficient melt extraction. We suggest the 2011–12 rhyolitic eruption was generated from a primitive basaltic crystal-rich mush that short-circuited the typical full range of magmatic differentiation in a single step.