ASCVac-1, a Multi-Peptide Chimeric Vaccine, Protects Mice Against Ascaris suum Infection

Control of human ascariasis, the most prevalent neglected tropical disease globally affecting 450 million people, mostly relies on mass drug administration of anthelmintics. However, chemotherapy alone is not efficient due to the high re-infection rate for people who live in the endemic area. The development of a vaccine that reduces the intensity of infection and maintains lower morbidity should be the primary target for infection control. Previously, our group demonstrated that immunization with crude Ascaris antigens in mice induced an IgG-mediated protective response with significant worm reduction. Here, we aimed to develop a multipeptide chimera vaccine based on conserved B-cell epitopes predicted from 17 common helminth proteomes using a bioinformatics algorithm. More than 480 B-cell epitopes were identified that are conserved in all 17 helminths. The Ascaris-specific epitopes were selected based on their reactivity to the pooled sera of mice immunized with Ascaris crude antigens or infected three times with A. suum infective eggs. The top 35 peptides with the strongest reactivity to Ascaris immune serum were selected to construct a chimeric antigen connected in sequence based on conformation. This chimera, called ASCVac-1, was produced as a soluble recombinant protein in an Escherichia coli expression system and, formulated with MPLA, was used to immunize mice. Mice immunized with ASCVac-1/MPLA showed around 50% reduced larvae production in the lungs after being challenged with A. suum infective eggs, along with significantly reduced inflammation and lung tissue/function damage. The reduced parasite count and pathology in infected lungs were associated with strong Th2 immune responses characterized by the high titers of antigen-specific IgG and its subclasses (IgG1, IgG2a, and IgG3) in the sera and significantly increased IL-4, IL-5, IL-13 levels in lung tissues. The reduced IL-33 titers and stimulated eosinophils were also observed in lung tissues and may also contribute to the ASCVac-1-induced protection. Taken together, the preclinical trial with ASCVac-1 chimera in a mouse model demonstrated its significant vaccine efficacy associated with strong IgG-based Th2 responses, without IgE induction, thus reducing the risk of an allergic response. All results suggest that the multiepitope-based ASCVac-1 chimera is a promising vaccine candidate against Ascaris sp. infections.

Preclinical Trial of Traditional Plant Remedies for the Treatment of Complications of Gestational Malaria

Background: Most pregnant women living in high malaria endemic regions of Nigeria use herbal remedies for the management of malaria-in-pregnancy, rather than the commonly prescribed drugs. Remedies common to this area involve a suspension of A. indica (AI) leaves and in some cases, a suspension containing a mixture of AI and D.edulis (PS). Aim: This study examined the therapeutic efficacies of AI, PS, or a combination of AI and PS in a pregnant rat model for exoerythrocytic stages of Plasmodium falciparum parasite. Method: A predetermined sample size of 30 dams was used (for a power level and confidence interval of 95%), and divided equally into six groups made up of non-malarous dams, untreated malarous dams, and malarous dams either treated exclusively with 1 mL of 3000 mg/kg b.w AI, 1000 mg/kg b.w PS, AI + PS (50% v/v), or 25 mg/kg b.w CQ. Result: No maternal mortality was recorded. AI significantly improved maternal weight gain from 32.4 to 82.2 g and placental weight from 0.44 to 0.53 g. In the curative test, AI and AI + PS significantly reduced the average percentage parasitemia (APP) in the pregnant rats from >80% to <20%. No significant difference in the APP was found between the pregnant rats treated with any of CQ or AI during the suppressive test. Results for the prophylactic test of the study groups showed that the APP was significantly reduced from 24.69% to 3.90% when treated with AI and 3.67% when combined with PS. AI + PS reduced diastolic blood pressure from 89.0 to 81.0 mm/Hg and compared with that of the non malarous dams. AI or AI + PS significantly increased the platelet counts (103 µL) from 214.1 to 364.5 and 351.2, respectively. AI and AI + PS improved birth weight from 2.5 to 3.9 g and crown rump length from 2.6 to 4.1 cm. For biomarkers of preeclampsia, combining AI and PS led to the reversal of the altered levels of creatine kinase, lactate dehydrogenase, cardiac troponin, soluble Fms-Like Tyrosine Kinase-1, and placental growth factor. Conclusions: This study validates the use of A. indica for the treatment of gestational malaria due to its antiplasmodial and related therapeutic effects and in combination with pear seeds for the management of malaria-in-pregnancy-induced preeclampsia.

Preclinical Trial of the Effectiveness of the Safety Nasogastric Tube to Detecting Tube Position Based on Tidal Volume and Pepsin Assay Results in the Gastrointestinal Tract of Macaca Fascicularis

Background: Generally, insertion of a nasogastric tube (NGT) does not use imaging guidance. This procedure has a risk of malposition to the lungs from 0.3–15%. The NGT verification only detects the position of the tube in the end of procedure. Misplacement of NGT into the respiratory tract can result in damage to the lungs. Safety nasogastric tube (SNGT) has been created to detect the position of the tube in real-time, simple, and inexpensive. This study aims to prove the effectiveness of the SNGT prototype in Macaca fascicularis. Result: The SNGT with an airbag size of 50% of tidal volume (SNGT 50% TV) had 100% sensitivity and specificity in detecting the position of the tube. While the SNGT with an airbag size of 100% of TV (SNGT 100% TV) has sensitivity of 100% and specificity of 87.5%. There was significant difference between the movement of airbag of SNGT 50% TV and SNGT 100% TV (p ≤ 0.05). However, there was no significant difference between the accuracy of placement of 50% TV SNGT, 100% TV SNGT, and conventional NGT (p > 0.05). The pepsin enzyme has better sensitivity (100%) than pH paper (91.66%) in detecting the end position of tube. Conclusion: SNGT tube has high effectiveness in detecting the position of the tube inside of the respiratory and digestive tracts to prevent misplacement.

Effectiveness of Guava Leaf Steep water against the bacterial growth of S. Mutans with Microdillution Method

Indonesia is famously known for its rich plant biodiversity with medicinal properties. Guava (Psidium guajava Linn.) is one of medicinal plants which can be used as alternative for treating diseases. Guava leaf contains flavonoids, saponins, and tannins, that can act as inhibitors against bacteria, antioxidants, and antibacterial. Numerous dental and oral diseases are caused by bacteria, one of which is dental caries. Principally, dental caries can be prevented by maintaining the oral cavity hygiene, chemically or mechanically, using antiseptics possessing antibacterial activities. The aim of this study was to investigate the effectiveness of guava leaves steep water against S. Mutans bacterium using microdilution method. The aim also included the investigation of inhibition concentration of guava leaves steep water. This research was experimental in nature, by using the guava leaves steep water as the sample with various concentrations (0.753%, 1.563%, 3.125%, 6.25%, 12.5%, 25%, 50%, 100%). S. Mutans was obtained from the laboratory of veterinary Universitas Syiah Kuala (Unsyiah). The results of this research revealed that the guava leaves steep water was effective in inhibiting S. Mutans with Minimum Inhibitory Concentration (MIC) of 6.25% In conclusion, we would like to investigate the guava leaves steep water as a mouthwash in our research with a preclinical trial.

Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies

With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.

A novel paclitaxel coated balloon with increased drug transfer for treatment of complex vascular lesions

Background Drug coated balloons (DCB) with paclitaxel (Ptx) dose of 2–3.5 μg/mm2 balloon surface inhibit restenosis with different effectiveness and duration of success. A clinical dose finding study is not known for any of the currently marketed products. The aim of the present preclinical trial was to investigate a novel DCB coated with 6 μg Ptx/mm2 in a porcine model. Methods and results The current study investigated a DCB with a novel, modified iopromide based matrix with 6 μg Ptx/mm2. Drug transfer to the vessel wall of peripheral arteries was compared with a dose of 3 μg Ptx/mm2 and two fully overlapping DCB with 3 μg Ptx/mm2, each. Ptx concentration in the vessel wall after drug transfer was about twice as high for balloons with 6 μg/mm2 (1957±1472 μg/g) and two overlapping DCB with 3 μg Ptx/mm2, each (1287±619 μg/g) compared to a single balloon with 3 μg Ptx/mm2, (787±738 μg/g), with statistical significant differences for 1x6 μg/mm2 vs. 1x3 μg/mm2 (p = 0.017) but not for 2x3 μg/mm2 vs. 1x3 μg/mm2 (p = 0.184) and 1x6 μg/mm2 vs. 2x3 μg/mm2 (p = 0.178). The proportion of residual Ptx on balloon after treatment was similar for all groups between 6±1% and 10±3% of dose on balloon. Conclusion The dose of 6 μg Ptx/mm2 was successfully as well as reproducibly coated on conventional balloon catheters. Increased Ptx on balloons resulted in increased drug concentration in the vessel wall. A single balloon with 6 μg Ptx/mm2 seems to provide double dose compared to 3 μg Ptx/mm2, facilitates the procedure, and may reduce medico-economic cost compared to the use of two standard DCB.

Novel Alhagi maurorum leaves mediated synthesis of titanium nanoparticles for human breast carcinoma applications: a preclinical trial

IntroductionIn this study, titanium nanoparticles (TiNPs) were synthesized in an aqueous medium using Alhagi maurorum extract as stabilizing and reducing agents.Material and methodsUltraviolet–visible spectrophotometry (UV-Vis), fourier-transform infrared spectroscopy (FTIR), X‐ray diffraction (XRD), scanning electron microscopy (SEM), and Energy Dispersive X-ray Spectrometry (EDS) were the techniques to characterize the biosynthetic of TiNPs. According to the XRD analysis. To survey the anti-human breast cancer effects of TiNPs, MTT assay was used on the common breast cancer cell lines i.e., breast cancer (Breast adenocarcinoma (MCF7), infiltrating ductal cell carcinoma (Hs 319.T), inflammatory carcinoma of the breast (UACC-732), and metastatic carcinoma (MDA-MB-453) cell lines.Results16.08 nm was measured for TiNPs crystal size. SEM images exhibited a uniform spherical morphology in range size of 12.16 to 43.46 nm for the biosynthesized nanoparticles respectively. The cell viability of breast carcinoma cells decreased dose-dependently in the titanium nanoparticles presence. The IC50 of A. maurorum and titanium particles on MCF7 cell line were 680 and 359 µg/mL, on Hs 319.T cell line were 507 and 191 µg/mL, on UACC-732 cell line were 477 and 217 µg/mL, and on MDA-MB-453cell line were 507 and 191 µg/mL, respectively. TiNPs had high anti-breast cancer activities dose-dependently against MCF7, Hs 319.T, UACC-732, and MDA-MB-453 cell lines.ConclusionsThe best result of anti-breast cancer effects was seen in the case of the Hs 319.T cell line.