Nicardipine Research Articles

Design, Formulation, and Optimization of Nicardipine-Loaded Gastroretentive Floating Microspheres: In-vitro, Ex-vivo and In-vivo Characterization.

Nicardipine hydrochloride is highly soluble at low pH values. The objective of this investigation was to design, manufacture, and refine the drug’s floating microspheres to increase its bioavailability and prolong its period of residence in the gastrointestinal tract. To optimize the Box-Behken and prepare the floating microspheres, solvent evaporation was employed. The formulation F5 was discovered to be the best as anticipated by the design expert software’s point prediction. Evaluations of pre- and postcompressional parameters were conducted. Utilizing several kinetic models, the drug release pathways were examined. The drugs and excipients did not interact, according to the FTIR/DSC investigations. According to the radiological approach, F5 showed good in-vitro buoyancy. The gastroretentive property of microspheres is revealed by X-ray pictures obtained at 2, 8, and 12 hours for the buoyancy investigation. F5 (235.04%) demonstrated a high relative bioavailability over oral tablets, according to the in-vivo pharmacokinetic investigation. In comparison to the marketed formulation group, the F5-treated group experienced a considerably larger percent decline in BP values (20.00 ± 6.00 and 13.00 ± 4.00%, respectively) at 36 and 48 hours of the in-vivo pharmacodynamic testing. For 90 days, the F5 formulation was maintained at 5 ± 2 and 25 ± 2°C, indicating the stability of nicardipine microspheres.

Nicardipine-chitosan nanoparticles alleviate thioacetamide-induced acute liver injury by targeting NFκB/NLRP3/IL-1β signaling in rats: Unraveling new roles beyond calcium channel blocking

Liver inflammatory diseases are marked by serious complications. Notably, nicardipine (NCD) has demonstrated anti-inflammatory properties, but its benefits in liver inflammation have not been studied yet. However, the therapeutic efficacy of NCD is limited by its short half-life and low bioavailability. Therefore, we aimed to evaluate the potential of NCD-loaded chitosan nanoparticles (ChNPs) to improve its pharmacokinetic profile and hepatic accumulation. Four formulations of NCD-ChNPs were synthesized and characterized. The optimal formulation (NP2) exhibited a mean particle diameter of 172.6 ± 1.94 nm, a surface charge of +25.66 ± 0.93 mV, and an encapsulation efficiency of 88.86 ± 1.17 %. NP2 showed good physical stability as a lyophilized powder over three months. It displayed pH-sensitive release characteristics, releasing 77.15 ± 5.09 % of NCD at pH 6 (mimicking the inflammatory microenvironment) and 52.15 ± 3.65 % at pH 7.4, indicating targeted release in inflamed liver tissues. Pharmacokinetic and biodistribution studies revealed that NCD-ChNPs significantly prolonged NCD circulation time and enhanced its concentration in liver tissues compared to plain NCD. Additionally, the study investigated the protective effects of NCD-ChNPs in thioacetamide-induced liver injury in rats by modulating the NFκB/NLRP3/IL-1β signaling axis. NCD-ChNPs effectively inhibited NFκB activation, reduced NLRP3 inflammasome activation, and subsequent release of IL-1β, which correlated with improved hepatic function and reduced inflammation and oxidative stress. These findings highlight the potential of NCD-ChNPs as a promising nanomedicine strategy for the treatment of liver inflammatory diseases, warranting further investigation into their clinical applications, particularly in hypertensive patients with liver inflammatory conditions.

Method development and validation of Nicardipine Hydrochloride injection and its related substances by RP-HPLC

Method development and validation of Nicardipine Hydrochloride injection and its related substances by RP-HPLC

Lipid-Polymer Hybrid Nanoparticles Synthesized via Lipid-Based Surface Engineering for a robust drug delivery platform

Herein, lipid-polymer core-shell hybrid nanoparticles composed of poly(D,L-lactic-co-glycolic acid) (PLGA)/lecithin (PLNs) were synthesized through lipid-based surface engineering. Lipids were absorbed onto the surface of the PLGA core to enhance the advantages of polymeric nanoparticles and liposomes. The amounts of lipids and encapsulation of the drug nicardipine hydrochloride (NCH) in the PLNs were studied. NCH-loaded PLNs (NCH-PLNs) were produced in high yield (66%) with a high encapsulation efficiency (92%) and a size of 176 nm. The mass of phosphorus (P) on the NCH-PLN surface was qualitatively and quantitatively investigated using X-ray fluorescence spectroscopy, and lecithin addition increased the P mass percentage due to the phosphate group (PO43-) in its structure. These data confirmed the lipid-based surface engineering of NCH-PLNs. The zeta potential of NCH-PLN exceeded −30 mV, ensuring colloidal stability, and preventing precipitation through electrostatic stabilization. In vitro, NCH was continuously and slowly released from NCH-PLNs over 16 days. Furthermore, PSVK1 cells exhibited high viability after treatment with NCH-PLNs, indicating favorable cytocompatibility. After comparing various mathematical equations of drug release kinetics, the data best fit the Korsmeyer-Peppas model with R2 values of 0.989, 0.990, and 0.982 for 1.0, 3.0, and 5.0 mg/mL lecithin, respectively. The release exponents obtained ranged from 0.480 to 0.505, suggesting anomalous transport release. Thus, NCH-PLNs have potential as a robust drug delivery platform for the controlled administration of NCH, particularly for vasodilation during neurosurgery.

Blood pressure lowering enhances cerebrospinal fluid efflux to the systemic circulation primarily via the lymphatic vasculature

BackgroundInside the incompressible cranium, the volume of cerebrospinal fluid is directly linked to blood volume: a change in either will induce a compensatory change in the other. Vasodilatory lowering of blood pressure has been shown to result in an increase of intracranial pressure, which, in normal circumstances should return to equilibrium by increased fluid efflux. In this study, we investigated the effect of blood pressure lowering on fluorescent cerebrospinal fluid tracer absorption into the systemic blood circulation.MethodsBlood pressure lowering was performed by an i.v. administration of nitric oxide donor (sodium nitroprusside, 5 µg kg−1 min−1) or the Ca2+-channel blocker (nicardipine hydrochloride, 0.5 µg kg−1 min−1) for 10, and 15 to 40 min, respectively. The effect of blood pressure lowering on cerebrospinal fluid clearance was investigated by measuring the efflux of fluorescent tracers (40 kDa FITC-dextran, 45 kDa Texas Red-conjugated ovalbumin) into blood and deep cervical lymph nodes. The effect of nicardipine on cerebral hemodynamics was investigated by near-infrared spectroscopy. The distribution of cerebrospinal fluid tracers (40 kDa horse radish peroxidase,160 kDa nanogold-conjugated IgG) in exit pathways was also analyzed at an ultrastructural level using electron microscopy.ResultsNicardipine and sodium nitroprusside reduced blood pressure by 32.0 ± 19.6% and 24.0 ± 13.3%, while temporarily elevating intracranial pressure by 14.0 ± 7.0% and 18.2 ± 15.0%, respectively. Blood pressure lowering significantly increased tracer accumulation into dorsal dura, deep cervical lymph nodes and systemic circulation, but reduced perivascular inflow along penetrating arteries in the brain. The enhanced tracer efflux by blood pressure lowering into the systemic circulation was markedly reduced (− 66.7%) by ligation of lymphatic vessels draining into deep cervical lymph nodes.ConclusionsThis is the first study showing that cerebrospinal fluid clearance can be improved with acute hypotensive treatment and that the effect of the treatment is reduced by ligation of a lymphatic drainage pathway. Enhanced cerebrospinal fluid clearance by blood pressure lowering may have therapeutic potential in diseases with dysregulated cerebrospinal fluid flow.

Revolutionizing Drug Delivery: Nicardipine Nanosuspension Formulation and In-Vitro Evaluation

Nicardipine hydrochloride, is a potent calcium channel blocker, is commonly used in the management of hypertension and angina. It is a BCS class II drug which has low aqueous solubility and high permeability. In the present study, an attempt was made to formulate and evaluate nanosuspension of Nicardipine hydrochloride using different stabilizers, namely Tween 80, PVP K30, Poloxamer 188 by using Nanoprecipitation method with the objective to improve solubility and enhance dissolution of Nicardipine hydrochloride. Prepared nanosuspensions were evaluated for drug-excipient compatibility, particle size, PDI (Polydispersity Index), Zeta potential, Drug content, Saturation solubility, In-vitro release study, Scanning electron microscopy (SEM). FTIR (Fourier Transform Infrared Spectroscopy) studies revealed the compatibility of the drug with excipients. Nanosuspension (F3), which had the lowest particle size and the highest % Drug Release, was selected as the optimum formulation. It showed the droplet size, PDI, ZP,% Drug content and %Drug release of 150.4 nm,0.243, -30.6 mV,95.52%,91.24%. Kinetic release profiles of the NS F3 revealed that it followed First order kinetics. This study showed the ability of nanosuspension system in improving the solubility and drug release of Nicardipine.
 Keywords: Nicardipine, Nanosuspension, Solubility, % Drug Release, % Drug content, Scanning electron microscopy.

A systematic review of nicardipine hydrochloride

A systematic review of nicardipine hydrochloride

Development of Sustained Release System Based on High Water-Absorbable Gel Formation Using Croscarmellose Sodium, Alkaline Excipients and HPMC (ACSH SR System); Novel Application of Croscarmellose Sodium as a Gel Former.

Croscarmellose sodium, generally used as a superdisintegrant in pharmaceutical formulations, is hydrolyzed to form the gel structure under basic pH conditions. Utilizing this property of croscarmellose sodium, we developed a novel sustained release (SR) system. Immediate release (IR) and SR tablets containing croscarmellose sodium, alkaline excipients and/or hydroxypropyl methylcellulose (HPMC) were prepared and examined for wet strength and in vitro drug release behavior. In vivo oral drug absorption was evaluated for IR tablets, HPMC tablets and our novel SR tablets in fasted Beagle dogs. To form the gel structure even under the physiological condition, alkaline excipients were added into the formulation containing croscarmellose sodium. Furthermore, HPMC was used to make the gel structure strong enough against mechanical destructive forces. The novel alkalized croscarmellose sodium-HPMC (ACSH) SR tablet, consisting of croscarmellose sodium, alkaline excipients, and HPMC, successfully sustained the release of acetaminophen, ibuprofen, or nicardipine hydrochloride, compared with the IR tablets. The ACSH SR system provided a better release of acetaminophen than the HPMC tablet without croscarmellose sodium in the release study using a small volume of liquid, suggesting that substantial release and subsequent absorption would be expected in the distal intestinal segments after oral dosing. The in vivo oral absorption study revealed that the ACSH SR system successfully suppressed and prolonged the plasma concentrations of acetaminophen. This novel ACSH SR system prepared with croscarmellose sodium, alkaline excipients, and HPMC, would be a promising SR formulation for enabling substantial drug absorption in the distal intestinal segments.

The effect on vital signs of concomitant administration of nicardipine and dexmedetomidine sedation after spinal anesthesia: A double-blind, randomized controlled trial.

We evaluated heart rate (HR) and blood pressure (BP) trends when nicardipine (NCD) was co-administered during dexmedetomidine (DEX) sedation after spinal anesthesia. Sixty patients aged 19 to 65 were randomly assigned to the DEX or DEX-NCD groups. Five minutes after infusion of the loading dose of DEX, the NCD was administered intravenously at a rate of 5 μg/kg for 5 minutes in the DEX-NCD group. The study starting point was set at 0 minute when the DEX loading dose was initiated. The primary outcomes were the differences in HR and BP between the 2 groups during the study drug administration. Secondary outcomes included the number of patients whose HR was < 50 beats per minute (bpm) after the DEX loading dose infusion, and associated factors were evaluated. The incidence of hypotension in the postanesthesia care unit, postanesthesia care unit length of stay, postoperative nausea and vomiting, postoperative urinary retention, time to first urination after spinal anesthesia, acute kidney injury, and postoperative hospital length of stay were evaluated. The HR was significantly higher at 14 minutes, and the mean BP was significantly lower at 10 minutes in the DEX-NCD group than in the DEX group. The number of patients with an HR < 50 bpm during surgery was significantly higher in the DEX group than in the DEX-NCD group at 12, 16, 24, 26, and 30 minutes. The DEX group and a low initial HR were independently associated with the occurrence of an HR < 50 bpm after DEX loading dose infusion. Postoperative outcomes were not significantly different between the 2 groups. Simultaneous administration of NCD during the administration of a loading dose of DEX prevented severe bradycardia. Co-administration of NCD may be considered in patients with a low initial HR when severe bradycardia is expected during the DEX loading dose infusion. NCD and DEX may be safely infused simultaneously without affecting postoperative complications (see Figure S1, Supplemental Digital Content, http://links.lww.com/MD/J241 , Graphical abstract).

Design, formulation, in-vitro and in-vivo pharmacokinetic evaluation of Nicardipine- nanostructured lipid carrier for transdermal drug delivery system

Nicardipine hydrochloride (NCP), a calcium channel blocker, may be useful for treating chronic stable angina and hypertension through a therapeutic transdermal system because it has a low dose, short half-life, and high first-pass metabolism. This study used a hydrogel incorporating nanostructured lipid carriers (NLCs) to enhance NCP retention and skin permeability. The NLCs formula was fine-tuned using a Central composite design with three factors and three levels. The effects of sonication time, lipid concentration, and surfactant concentration on particle size, Entrapment Efficiency (EE), and polydispersity index (PDI) were also studied. There were two main components to the strategy that allowed it to succeed. Mean particle size in the optimized formulation was 107.78 nm, and the entrapment efficiency was 70.52%. Drug loading was 6.59%. A pharmaceutical release research discovered that NCP has a half-life of 10 h in vitro. The selected formulation was then placed into a Carbopol gel, and ex-vivo permeation studies showed that the gel with NLCs provided more penetration (66.45%) and longer sustained release (up to 11 h) than the free drug-based gel. The gel used in NLCs is especially notable for limiting systemic access and minimizing the risk of side effects from free drug. The in-vivo absorption study shown that NCP bioavailability was greatly improved in wistar rats. Using an experimental methodology, we found that NCP-NLCs could efficiently transport NCP across the skin by transdermal injection, and that there was a quadratic relationship between the variables of interest.

Successful Recovery from Severe Fever with Thrombocytopenia Syndrome and Hemophagocytic Lymphohistiocytosis with Standard Treatment and a Calcium Channel Blocker of Nicardipine Hydrochloride: A Case Report.

A 67-year-old man was admitted to our hospital with a high fever. Laboratory tests revealed leukopenia, thrombocytopenia, liver dysfunction, rhabdomyolysis, and hyperferritinemia. He was diagnosed with severe fever with thrombocytopenia syndrome (SFTS) complicated by hemophagocytic lymphohistiocytosis and treated with steroid therapy, intravenous calcium channel blocker (CCB), and supportive care, without favipiravir. Serum levels of ferritin and soluble interleukin 2 receptor (sIL2R) were markedly elevated on Day 3 after admission and decreased thereafter, while an SFTS viral load of 6.8×104 copies/μL was detected on Day 2, increasing to 2.9×105 copies/μL on Day 6. Serum ferritin and sIL2R levels may be better indicators of mortality than the SFTS viral load, and CCBs may have a therapeutic effect.

Development of an Oral Liquid Formulation of Nicardipine Hydrochloride Compounded with Simple Excipients for the Treatment of Pediatric Hypertension

Nicardipine hydrochloride is an anti-hypertensive drug that is used off-label to treat hypertension in children. A previous oral formulation of nicardipine hydrochloride was developed using a commercial vehicle as an excipient. However, ready-to-use vehicles are prone to supply shortages, and their composition may undergo substantial modifications. The aim of this study was to propose a new oral formulation of nicardipine hydrochloride 2 mg/mL using simple excipients. The formulation included hydroxypropylmethylcellulose, simple syrup, polysorbate 80, sodium saccharin, citrate buffer, strawberry flavor and 0.2% potassium sorbate. The uniformity of content was maintained before and after agitation. Nicardipine hydrochloride concentration assessed by HPLC-MS/MS remained above 90% for 365 days before opening and for 28 days after opening. pH and osmolality were maintained throughout the study, and no microbial contamination was observed. The uniformity of mass of the delivered doses was evaluated using four different devices. A new oral formulation of nicardipine hydrochloride 2 mg/mL was developed using simple and safe excipients. Pharmacological and clinical parameters remain to be assessed and compared with those of the previous formulation.

FORMULATION AND IN-VITRO EVALUATION OF NICARDIPINE HYDROCHLORIDE BILAYERED TABLET FOR CONTROLLED RELEASE

The aim of present research work was to prepare and evaluate the controlled release bilayered tablet of Nicardipine HCL to improve its bioavailability for the treatment of hypertension. To minimize critical process parameters, two layer compression method was used for the formulation of Bilayered tablets. The appropriate formulation was achieved successfully with the combination of Polymers MCC, Carbopol 71G and HPMC K100M produced desired release profile for Metoprolol succinate extended release layer. The combination of disintegrating agents that is Sodium starch glycolate and Dicalcium phosphate produced desired release rate for Nicardipine immediate release layer. The results reveal that formulation F7 has met the objective of controlled drug release for over a period of 12 hrs. The formulation F7 ascertained the efficacy of the controlled released Bilayered tablet of Nicardipine and Metoprolol ER tablet in hypertension. This sustained release Bilayered tablet with the combination of Nicardipine and metoprolol can be used in the management of different types of hypertension. The formulation F7 of combination of Nicardipine and metoprolol showed controlled release profile among the other, Hence it was considered as an optimized formulation.

Insights for applying N,S-doped carbon dots as a fluorescent nanoprobe for estimation of some nitro-calcium channel blockers.

A facile and simple one-step hydrothermal approach was adopted for fabrication of N and S co-doped carbon quantum dots probe (NSCDs) by using thiosemicarbazide as a dopant and citric acid as a precursor. The prepared NSCDs with a high quantum yield of 0.58 were characterized using UV–visible spectroscopy, IR spectroscopy and high-resolution transmission electron microscopy. The as-obtained NSCDs could be deemed as an effective fluorescent nanosensor for the determination of some anti-hypertensive nitro-calcium channel blockers (Nitro-CCBs) including nicardipine (NIC), nifedipine (NIF) and nimodipine (NIM) whether in pure form or in their pharmaceutical formulations. Measurements of NSCD emission intensity were performed at 416 nm after being excited at 345 nm. Nitro-CCBs could induce quenching in the native fluorescence of NSCDs due to the inner filter effect and static quenching mechanism. The studied compounds were investigated within linear detection range of (10.0–100.0 µM) for NIC, (5.0–60.0 µM) for NIF and (5.0–60.0 µM) for NIM. Correlation coefficients are greater than or equal to 0.9998 and detection limits are ranged between 0.55 and 1.86 µM. The proposed method was extended to estimate the studied compounds in different pharmaceutical samples with high % recoveries ranging from (97.95 to 101.28%) and low % relative standard deviation values (less than 2%). Validation of the developed spectrofluorimetric method was done along with the International Council of Harmonization requirements.

Bioavailability Study of Developed S-SMEDDS Formulation for Nicardipine Hydrochloride in Rats

Aim of the current research work to conduct bio availability of Nicardipine Hydrochloride S-SMEDDS in rats, compare with pure drug and Marketed Formulation. Study is conducted by using Wistar rats. 3-Groups were divided into Set-A Pure Drug, Set B: Marketed formulation, Set C: Optimized formulation, Total 18 healthy rats were selected, 6 in each group with weight of 300±50g Rats were labeled by numbers. Blood samples were collected from Tail vein method at pre-determined time intervals then blood samples were analyzed by validated HPLC method. S-SMEDDS exhibit cmax at 1429.58±107.40ng/mL, tmax at 0.75Hr, AUC(0-t) at 3042.05±333.35 ng. min/ml and t1/2 at 3.49±0.016 hr. AUC and maximum plasma concentration of the S-SMEDDS is higher than pure Nicardipine Hydrochloride drug and marketed formulation it indicates S-SMEDDS produce more bioavailability than Nicardipine Hydrochloride powder.

Formulation and Evaluation of Floating In-Situ Gel of Nicardipine Hydrochloride

The present research work aimed to formulate and evaluate a gastro retentive in situ gelling system of Nicardipine Hydrochloride using Sodium Alginate as gelling polymer, HPMC K100M as release retard polymer, calcium carbonate as a cross-linking agent, and tri-sodium citrate as fluidity enhancer agent to treat hypertension. The mechanism for the floatation was based on ionic cross-linking. Several evaluation tests were carried out for pre and final formulation evaluation. Based on the outcomes white-colored, viscous solution of uniform consistency was obtained. Batch B1 was very well prepared for the ability to control long-term drug release. The drug content was found to be &gt; 97 %, the viscosities were in the acceptable range suitable for swallowing, and pH was found to be in the range of 7.33 – 7.68 which was compatible with oral digestion. Design expert 13 Software was used to derive results of interaction and responses based on the concentration of polymer and statistical analysis. The optimized formulation i.e., Batch B1 (0.6 % w/v and 0.5 % w/v HPMC K100M) showed a slow drug release of 96.44 % up to 12 hours. The best fit model for the drug release followed the Higuchi model which explained that the drug release occurred by the Fiskian mechanism i.e., a combination of both diffusion and erosion. The in-situ gel prepared can ultimately provide prolonged release, enhance the bioavailability of the drug and increase patient compliance.&#x0D; Keywords: - In situ gel, Ionic cross linking, Sodium alginate, HPMC K100M, Nicardipine Hydrochloride.

Clinical efficacy and safety of two concentrations of intravenous nicardipine hydrochloride for nicardipine-related phlebitis in patients with preeclampsia.

To evaluate the effect of two concentrations of intravenous administration of nicardipine hydrochloride on nicardipine-related phlebitis in patients with preeclampsia. A total of 100 preeclampsia patients were administered with nicardipine hydrochloride and divided into the low-concentration (LC) and high-concentration (HC) groups. The incidence and severity of phlebitis, time from treatment to onset of phlebitis, skin temperature, visual analogue scale (VAS) score, induration, and systemic adverse reactions were compared between two groups. The incidence rate of phlebitis in the LC group was 20% (10/50), significantly lower than 42% (21/50) in the HC group (P< 0.05). Ridit Analysis showed that the severity of phlebitis in the LC group was remarkably lower than that in the HC group (P< 0.05). In the LC group, the time from intravenous administration to onset of phlebitis was longer, the average skin temperature was higher, the VAS score was lower, and the indurated area was smaller than those in the HC group (all P< 0.05). Intravenous infusion of nicardipine hydrochloride with constant and low concentration reduces the incidence rate of phlebitis, prolongs the time from treatment to onset of phlebitis, alleviates the severity of phlebitis and pain, maintains skin temperature, and minimizes induration in preeclampsia patients without systemic adverse reactions.

Protein-assisted biomimetic synthesis of nanoscale gadolinium-integrated polypyrrole for synergetic and ultrasensitive electrochemical assays of nicardipine in biological samples

Electrically conductive polymer nanomaterials signify a promising class of sensing platforms in the field of electrochemistry, but their applications as electrocatalysts are commonly limited by their poor colloidal stability in aqueous media and large particle sizes. Inspired by biomineralization approaches for integrating nanoscale materials, herein, a gadolinium (Gd)-integrated polypyrrole (PPy) electrocatalyst (namely, BSA@PPy-Gd) was successfully prepared by choosing bovine serum albumin (BSA) as a stabilizer for biomimetic mineralization and polymerization in a “one-step” manner. BSA@PPy-Gd possesses outstanding water dispersibility, nanoscale morphology, and improved electrical conductivity. The electrocatalytic competency of the electrochemical (EC) sensing platform fabricated for the sensitive detection of nicardipine (NCD) was assessed. The synergy of remarkable conductivity, superior active surface area, and electrostatic interactions stimulated by the combination of BSA with the NH group of PPy on BSA@PPy-Gd and Gd increases the fast electron transfer at the analyte-electrode junction. The fabricated EC sensor, BSA@PPy-Gd/glassy carbon electrode (GCE), exhibits a current intensity greater than that of PPy/GCE, BSA/GCE, and bare GCE in terms of peak height at a pH of 7.0 in phosphate buffer solution. The newly fabricated EC sensing platform shows excellent electrocatalytic activities for the electroreduction of NCD in terms of a low detection limit (2 nM), good sensitivity, linear dynamic detection ranges (0.01–575 μM), operational stability, and repeatability and was also tested on rat and human serum specimens.

Cardiac dysfunction affects eye development and vision by reducing supply of lipids in fish

Developing organisms are especially vulnerable to environmental stressors. Crude oil exposure in early life stages of fish result in multiple functional and developmental defects, including cardiac dysfunction and abnormal and smaller eyes. Phenanthrene (Phe) has a reversible impact on cardiac function, and under exposure Phe reduces cardiac contractility. Exposure to a known L-type channel blocker, nicardipine hydrochloride (Nic) also disrupts cardiac function and creates eye deformities. We aimed to investigate whether cardiac dysfunction was the major underlying mechanism of crude oil-, Phe- and Nic-induced eye malformations. We exposed Atlantic haddock (Melanogrammus aeglefinus) early embryos to Nic and crude oil (Oil) and late embryos/early larvae to Phe exposure. All three exposures resulted in cardiac abnormalities and lead to severe, eye, jaw and spinal deformities at early larval stages. At 3 days post hatching, larvae from the exposures and corresponding controls were dissected. Eyes, trunk, head and yolk sac were subjected to lipid profiling, and eyes were also subjected to transcriptomic profiling. Among most enriched pathways in the eye transcriptomes were fatty acid metabolism, calcium signaling and phototransduction. Changes in lipid profiles and the transcriptome suggested that the dysfunctional and abnormal eyes in our exposures were due to both disruption of signaling pathways and insufficient supply of essential fatty acids and other nutrients form the yolk.

Hypertensive cerebral hemorrhage with undetectable plasma vascular endothelial growth factor levels in a patient receiving intravitreal injection of aflibercept for bilateral diabetic macular edema: a case report

BackgroundIntravitreal injections of anti-vascular endothelial growth factor are commonly used to treat macular diseases, including diabetic macular edema. Anti-vascular endothelial growth factor drugs can enter the systemic circulation after intravitreal injections and appear to suppress circulating vascular endothelial growth factor levels. However, whether this can cause any systemic adverse events remains unknown.Case presentationA 70-year-old Japanese man diagnosed with diabetic macular edema in both eyes was treated with anti-vascular endothelial growth factor intravitreal injections. One month after receiving two intravitreal injections of aflibercept 1 week apart for diabetic macular edema in both eyes, he complained of a severe acute headache. The patient was diagnosed with hypertensive cerebral hemorrhage of the occipital lobe based on an elevated blood pressure of 195/108 mmHg and the results of computed tomography and magnetic resonance imaging of his brain. The patient was treated with an intravenous injection of nicardipine hydrochloride to lower his systemic blood pressure. Two days after the stroke, the patient began oral treatment with 80 mg/day telmisartan, which was continued for 3 days, and the telmisartan dose was reduced to 40 mg/day thereafter. His blood pressure promptly dropped to 130/80 mmHg, and his severe headache disappeared. One year after the cerebrovascular stroke, the telmisartan was discontinued because his blood pressure stabilized at a normal level. His plasma vascular endothelial growth factor levels were measured via specific enzyme-linked immunosorbent assay before and after the intravitreal injections of aflibercept. Immediately before the injections, the vascular endothelial growth factor level was 28 pg/ml, but it rapidly fell below the detection limit within 1 week, where it remained for over 2 months. Two days before the cerebral hemorrhage, his plasma vascular endothelial growth factor level was below the detection limit, and 2 months later after the stroke, his plasma vascular endothelial growth factor level recovered to 41 pg/ml.ConclusionThis case suggests that hypertension and resultant cerebral hemorrhage can occur in patients with diabetic macular edema when plasma vascular endothelial growth factor levels are systemically decreased below the detection limit for a prolonged time after local injections of anti-vascular endothelial growth factor agents into the vitreous cavity. Therefore, severely reduced plasma vascular endothelial growth factor levels could be a higher risk factor to develop generally infrequent stroke. Ophthalmologists should be aware of possible severe reduction of plasma vascular endothelial growth factor levels and resultant increase in blood pressure after intravitreal injections of an anti-vascular endothelial growth factor drug. If the plasma vascular endothelial growth factor levels could be monitored more easily and quickly during the treatment, it would help to prevent adverse events.