Search

Drugs exhibiting nonlinear pharmacokinetics hold significant importance in drug research and development. However, evaluating drug exposure accurately is challenging with the current formulae established for linear pharmacokinetics. This article aims to investigate the steady-state drug exposure for a one-compartment pharmacokinetic (PK) model with sigmoidal Hill elimination, focusing on three key topics: the comparison between steady-state drug exposure of repeated intravenous (IV) bolus ( AUC ss ) and total drug exposure after a single IV bolus ( AUC 0 - ∞ ); the evolution of steady-state drug concentration with varying dosing frequencies; and the control of drug pharmacokinetics in multiple-dose therapeutic scenarios. For the first topic, we established conditions for the existence of AUC ss , derived an explicit formula for its calculation, and compared it with AUC 0 - ∞ . For the second, we identified the trending properties of steady-state average and trough concentrations concerning dosing frequency. For the third, we developed formulae to compute dose and dosing time for both regular and irregular dosing scenarios. As an example, our findings were applied to a real drug model of progesterone used in lactating dairy cows. In conclusion, these results provide a theoretical foundation for designing rational dosage regimens and conducting therapeutic trials. [ABSTRACT FROM AUTHOR]

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1–14, 3–14, 5–14, or 7–14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1–3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.

Background: Only a small percentage of patients with acute stroke are currently eligible for thrombolysis, partly due to severe delays in hospital arrival. We had previously conducted the first regional study to assess the factors delaying acute stroke care in India. The present study aims to understand and describe in depth the variables associated with prehospital delay among patients admitted with an acute ischemic stroke. Methods: Data were prospectively collected by conducting an in-depth interview of 470 acute ischemic stroke patients and their bystanders, aged above 18 years, presenting to the Department of Emergency Medicine, Jubilee Mission Medical College and Research Institute, Thrissur. Patients who arrived within 4.5 h of symptom onset were considered as “early arrival” and those who arrived after 4.5 h were considered as “delayed arrival.” Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation. Results: Of the 470 patients who met the inclusion criteria, 73 patients reached within 4.5 h (15.5%), whereas 397 patients arrived after 4.5 h. The mean age of acute stroke patients who reached within 4.5 h was 63 ± 13.7 years, whereas the mean age of those who reached after 4.5 h was 63 ± 12.1 years. Binary logistic regression performed to quantify the associations of prehospital factors showed an increased risk of prehospital delay among individuals with lack of awareness (odds ratio [OR] = 5.16 [3.040–8.757], P < 0.001), followed by those for whom a vehicle was not available at the site of event (OR = 3.745 [1.864–7.522], P < 0.001). Within the predefined socioeconomic strata, compared to lower class, upper middle class had less risk (OR = 0.135 [0.018–1.035], P = 0.054), whereas the distance from first medical contact to emergency department contributed moderate risk (OR = 1.071 [1.028–1.116], P < 0.001) for prehospital delay. Conclusions: Health promotion techniques that increase public knowledge about the early signs of stroke, transferring patients directly to hospitals with thrombolysis capabilities, and making ambulance services more widely available are appropriate measures to reduce prehospital delay.

The oral delivery in English way was the very popular method, due to the ready taking of medicine and administration process. After oral administration of a drug, the process of its bioavailability being influenced by its stay in stomach are imperative. Lately, gastroretentive drug delivery systems (GRDDS) have been extensively used for drugs with a narrow absorption window, an inability to formulate the dose at high pH due to decreased stability and increasing solubility at low pH level Such drugs are the part of the design of medicine system that keeps for a while in the stomach and upon release of its active components causes the desired effect in the stomach. Achieving the desired result of gastric retention of drugs may be done through the use of agents of effervescence, mucoadhesive polymers, magnetic matter, bouncy enhancing carriers, along with a method which is effective in forming plug-like substances that are resistant to emptying of the stomach. Such conclusion records a concise viewpoint about the essential attributes of the latest individually addressed procedures on GRDDS. [ABSTRACT FROM AUTHOR]

Background: Only a small percentage of patients with acute stroke are currently eligible for thrombolysis, partly due to severe delays in hospital arrival. We had previously conducted the first regional study to assess the factors delaying acute stroke care in India. The present study aims to understand and describe in depth the variables associated with prehospital delay among patients admitted with an acute ischemic stroke. Methods: Data were prospectively collected by conducting an in-depth interview of 470 acute ischemic stroke patients and their bystanders, aged above 18 years, presenting to the Department of Emergency Medicine, Jubilee Mission Medical College and Research Institute, Thrissur. Patients who arrived within 4.5 h of symptom onset were considered as "early arrival" and those who arrived after 4.5 h were considered as "delayed arrival." Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation. Results: Of the 470 patients who met the inclusion criteria, 73 patients reached within 4.5 h (15.5%), whereas 397 patients arrived after 4.5 h. The mean age of acute stroke patients who reached within 4.5 h was 63 ± 13.7 years, whereas the mean age of those who reached after 4.5 h was 63 ± 12.1 years. Binary logistic regression performed to quantify the associations of prehospital factors showed an increased risk of prehospital delay among individuals with lack of awareness (odds ratio [OR] = 5.16 [3.040--8.757], P < 0.001), followed by those for whom a vehicle was not available at the site of event (OR = 3.745 [1.864--7.522], P < 0.001). Within the predefined socioeconomic strata, compared to lower class, upper middle class had less risk (OR = 0.135 [0.018--1.035], P = 0.054), whereas the distance from first medical contact to emergency department contributed moderate risk (OR = 1.071 [1.028--1.116], P < 0.001) for prehospital delay. Conclusions: Health promotion techniques that increase public knowledge about the early signs of stroke, transferring patients directly to hospitals with thrombolysis capabilities, and making ambulance services more widely available are appropriate measures to reduce prehospital delay. [ABSTRACT FROM AUTHOR]

Background: To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 μs) over conventional pulse width DBS (cDBS; ≥60 μs) in movement disorders. Objective: To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. Methods: We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. Results: Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p

To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 μs) over conventional pulse width DBS (cDBS; ≥60 μs) in movement disorders. To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p < 0.001) and ET (SMD = −0.71, p < 0.001), but the TW in terms of charge per pulse (CPP) did not differ. In PD, no differences were found in therapeutic and side effects (MDS-UPDRS-III, speech and gait, dyskinesia, non-motor symptoms and quality of life). In ET, Fahn-Tolosa-Marin Tremor Rating Scale was lower with spDBS vs. cDBS (SMD = 0.36, p < 0.001). A qualitative analysis suggested fewer stimulation-induced side effects with spDBS. CPP was lower with spDBS vs. cDBS in PD (SMD = 0.79, p < 0.001) and ET (MD = 46.46 nC, p < 0.001), but real-world data on battery longevity are lacking. Although spDBS enlarges the TW as a wider amplitude range in both PD and ET, it does not alter TW defined by CPP. The therapeutic efficacy of spDBS is not different from cDBS in PD, but spDBS apparently induces more tremor reduction in ET. • Short pulse width DBS (spDBS) in movement disorders widens the amplitude-based therapeutic window. • SpDBS in movement disorders does not alter the therapeutic window defined by CPP. • In Parkinson's disease, spDBS seems non-inferior as to therapeutic and side effects. • In essential tremor (ET), spDBS appears superior as to therapeutic and side effects. • Future long-term studies on spDBS should address dystonia, battery longevity and ET habituation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Opioid-induced respiratory depression limits the use of μ- opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy. Experimental Approach: Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays. Key Results: Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds. Conclusion and Implications: In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings. [ABSTRACT FROM AUTHOR]

Background Valproic acid, as a mood stabilizer, has been extensively used for the treatment of bipolar disorder and other psychiatric conditions. Although therapeutic drug monitoring (TDM) of valproic acid has been carried out at home and abroad for many years, controversies persist regarding the influence of age, sex and other factors on its plasma concentration. Objective To analyze the TDM results of valproic acid, providing a reference for rationalized individualized treatment of bipolar disorders or other psychiatric conditions. Methods Through the laboratory information system of Ruimei Medical Laboratory, information on TDM of valproic acid in outpatients and inpatients (including the patient's age, sex, TDM raw data, monitoring samples, and monitoring frequency) was obtained from Xi'an Mental Health Center from 2019 to 2021. The plasma concentration of valproic acid was classified into three categories (100 mg/L) according to the therapeutic window range recommended in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology (hereinafter referred to as AGNP Consensus) , and the percent of each category was calculated. And subsequent data analysis was performed using MedCalc 5.2. Results A total of 2 431 patients were monitored 2 992 times for understanding valproic acid treatment status, of which 1 637 were for men, and 1 355 for women. The frequencies of TDM of valproic acid increased by 54.93% in 2020 and 44.00% in 2021 compared to those reported in 2019. The proportion of patients who received only once was about 74.41%. Compared with inpatients, outpatients had higher prevalence of receiving one TDM of valproic acid (χ2=95.15, P0.05) . For each study year 2019-2021, the proportion of plasma concentration of valproic acid within the therapeutic window was 57.72%, which was significantly higher than that of the proportion of below and above the therapeutic window (χ2=155.38, 1 216.68, P100 mg/L) had statistically significant differences between different age and gender groups, and over the years (P

Interventional radiotherapy (IRT, brachytherapy) is a highly effective treatment method for non-melanoma skin cancer (NMSC). Traditionally, the maximum depth of NMSC lesions considered eligible for contact IRT was 5 mm; however, following several national surveys and recent recommendations, such cut-off, lesions thicker than 5 mm may be treated by contact IRT. The use of image guidance in defining the actual depth in treating NMSC to correctly identify clinical target volume (CTV) and prevent unnecessary toxicity is of paramount importance. The aim of the paper was to describe a multilayer arrangement of catheters to treat NMSC lesions thicker than 5 mm, thus proposing an example of dynamic intensity modulated IRT, using different catheter-to-skin distance of sources to reach the best CTV coverage and maximally reduce the excess of dose to the skin.

Radiotherapy is an effective therapy in tumour treatment. However, the characteristics of the tumour microenvironment, including hypoxia, low pH, and interstitial fluid pressure bring about radioresistance. To improve the anti-tumour effect of radiotherapy, it has been demonstrated that antiangiogenic therapy can be employed to repair the structural and functional defects of tumour angiogenic vessels, thereby preventing radioresistance or poor therapeutic drug delivery. In this study, we prepared triptolide (TP)-loaded Asn-Gly-Arg (NGR) peptide conjugated mPEG2000-DSPE-targeted liposomes (NGR-PEG-TP-LPs) to induce tumour blood vessel normalisation, to the end of increasing the sensitivity of tumour cells to radiotherapy. Further, to quantify the tumour vessel normalisation window, the structure and functionality of tumour blood vessels post NGR-PEG-TP-LPs treatment were evaluated. Thereafter, the anti-tumour effect of radiotherapy following these treatments was evaluated using HCT116 xenograft-bearing mouse models based on the tumour vessel normalisation period window. The results obtained showed that NGR-PEG-TP-LPs could modulate tumour vascular normalisation to increase the oxygen content of the tumour microenvironment and enhance the efficacy of radiotherapy. Further, liver and kidney toxicity tests indicated that NGR-PEG-TP-LPs are safe for application in cancer treatment [ABSTRACT FROM AUTHOR]

[Display omitted] Throughout the last decade, interventions to engineer the immune system called immunotherapy have revolutionized the fields of oncology and autoimmune disease. Researchers are developing platforms that enable new modes of immunotherapy and expand the current limitations by incorporating non-intravenous delivery strategies. Recent advances in the immunotherapy include the use of chemokines to direct immune cells into tumors, alternative combinatorial therapies, and oncolytic viruses. Similarly, there have been significant breakthroughs in the design and understanding of new biocompatible hydrogel-based materials for diverse biomedical applications, including large molecule drug delivery. In this review, we discuss how hydrogel platforms can enable modes of immunotherapy that are otherwise not feasible. Despite the many pre-clinical successes of hydrogels for the delivery of immunotherapies for treatment of cancer, hydrogels still face challenges in getting to the clinic and eventually approved. Herein we examine the application of hydrogels in high concentration subcutaneous, intratumoral, peritumoral, intraperitoneal, intracranial, and pulmonary delivery of immunotherapies. By analyzing the results of many pre-clinical hydrogel-enabled immunotherapy studies, we describe that local hydrogel delivery is a promising approach to increase the efficacy and decrease systemic toxicities of immunotherapies. We also discuss the application of hydrogels for synergistic combinatorial immunotherapy. Furthermore, we summarize the advancements and obstacles in local intratumoral administration and sustained release of immunotherapy-loaded hydrogels. Finally, we discuss challenges in the translational research, clinical development, and manufacturing of hydrogels which must be addressed to advance the field. [ABSTRACT FROM AUTHOR]

Interventional radiotherapy (IRT, brachytherapy) is a highly effective treatment method for non-melanoma skin cancer (NMSC). Traditionally, the maximum depth of NMSC lesions considered eligible for contact IRT was 5 mm; however, following several national surveys and recent recommendations, such cut-off, lesions thicker than 5 mm may be treated by contact IRT. The use of image guidance in defining the actual depth in treating NMSC to correctly identify clinical target volume (CTV) and prevent unnecessary toxicity is of paramount importance. The aim of the paper was to describe a multilayer arrangement of catheters to treat NMSC lesions thicker than 5 mm, thus proposing an example of dynamic intensity modulated IRT, using different catheter-to-skin distance of sources to reach the best CTV coverage and maximally reduce the excess of dose to the skin. [ABSTRACT FROM AUTHOR]

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRβ for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury. [ABSTRACT FROM AUTHOR]

The study of gene therapies has been of particular interest in recent decades due to their promising potential to slow or even rescue the degeneration of the retina in inherited retinal dystrophies (IRDs). Here, we review the current approaches to gene therapy trials on IRDs, including the selection of animal models, therapeutic window, vectors and dosages. Mice are typically the first choice of animal models and recombinant adeno-associated virus (rAAV) of serotype 8 is the most common vector for loss-of-function IRDs. Furthermore, the therapeutic window should be considered to ensure efficacy before retinal degeneration occurs if possible, and dosages must be tailored to each approach.

Immunotoxins (ITs), which are toxin-fused tumor antigen-specific antibody chimeric proteins, have been developed to selectively kill targeted cancer cells. The epidermal growth factor receptor (EGFR) is an attractive target for the development of anti-EGFR ITs against solid tumors due to its overexpression on the cell surface of various solid tumors. However, the low basal level expression of EGFR in normal tissue cells can cause undesirable on-target/off-tumor toxicity and reduce the therapeutic window of anti-EGFR ITs. Here, based on an anti-EGFR monobody with cross-reactivity to both human and murine EGFR, we developed a strategy to tailor the anti-EGFR affinity of the monobody-based ITs carrying a 24-kDa fragment of Pseudomonas exotoxin A (PE24), termed ER-PE24, to distinguish tumors that overexpress EGFR from normal tissues. Five variants of ER-PE24 were generated with different EGFR affinities (KD ≈ 0.24 nM to 104 nM), showing comparable binding activity for both human and murine EGFR. ER/0.2-PE24 with the highest affinity (KD ≈ 0.24 nM) exhibited a narrow therapeutic window of 19 pM to 93 pM, whereas ER/21-PE24 with an intermediate affinity (KD ≈ 21 nM) showed a much broader therapeutic window of 73 pM to 1.5 nM in in vitro cytotoxic assays using tumor model cell lines. In EGFR-overexpressing tumor xenograft mouse models, the maximum tolerated dose (MTD) of intravenous injection of ER/21-PE24 was found to be 0.4 mg/kg, which was fourfold higher than the MTD (0.1 mg/kg) of ER/0.2-PE24. Our study provides a strategy for the development of IT targeting tumor overexpressed antigens with basal expression in broad normal tissues by tailoring tumor antigen affinities. [ABSTRACT FROM AUTHOR]

Pesticide action is predominantly measured as a toxicological outcome, with pharmacological impact of sublethal doses on bystander species left largely undocumented. Likewise, chronic exposure, which often results in responses different from acute administration, has also been understudied. In this article, we propose the application of standard pharmacological principles, already used to establish safe clinical dosing regimens in humans, to the 'dosing of the environment'. These principles include relating the steady state dose of an agent to its beneficial effects (e.g. pest control), while minimising harmful impacts (e.g. off‐target bioactivity in beneficial insects). We propose the term 'environmental therapeutic window', analogous to that used in mammalian pharmacology, to guide risk assessment. To make pharmacological terms practically useful to environmental protection, quantitative data on pesticide action need to be made available in a freely accessible database, which should include toxicological and pharmacological impacts on both target and off‐target species. [ABSTRACT FROM AUTHOR]

Immunotoxins (ITs) are recombinant chimeric proteins that combine a protein toxin with a targeting moiety to facilitate the selective delivery of the toxin to cancer cells. Here, we present a novel strategy to enhance the cytosolic access of ITs by promoting their dissociation from target receptors under the reducing conditions of the endocytic pathway. We engineered monobody SS , a human fibronectin type III domain-based monobody with disulfide bond (SS)-containing paratopes, targeting receptors such as EGFR, EpCAM, Her2, and FAP. Monobody SS exhibited SS-dependent target receptor binding with a significant reduction in binding under reducing conditions. We then created monobody SS -based ITs carrying a 25 kDa fragment of Pseudomonas exotoxin A (PE25), termed monobody SS -PE25. These ITs showed dose-dependent cytotoxicity against target receptor-expressing cancer cells and a wider therapeutic window due to higher efficacy at lower doses compared to controls with SS reduction inhibited. ER SS /28-PE25, with a K D of 28 nM for EGFR, demonstrated superior tumor-killing potency compared to ER/21-PE25, which lacks an SS bond, at equivalent and lower doses. In vivo, ER SS /28-PE25 outperformed ER/21-PE25 in suppressing tumor growth in EGFR-overexpressing xenograft mouse models. This study presents a strategy for developing solid tumor-targeting ITs using SS-containing paratopes to enhance cytosolic delivery and antitumor efficacy. [Display omitted] • We engineered target-specific monobody SS with disulfide bond(SS)-containing paratopes. • Monobody SS showed SS-dependent binding and reduced binding under reducing conditions. • Monobody SS -PE25 ITs exhibit dose-dependent killing with a wider therapeutic window. • ER SS /28-PE25 demonstrated superior in vivo antitumor potency over ER/21-PE25. • Promoting IT dissociation in endosomes boosts its cytosolic delivery and potency. [ABSTRACT FROM AUTHOR]

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1–14, 3–14, 5–14, or 7–14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1–3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI. [Display omitted] • Delayed simvastatin treatment in the subacute phase promoted rehabilitation after TBI. • Simvastatin decreased TBI-induced production of ELOVL1 and VLCFAs. • Astrocytic ELOVL1 overexpression attenuated the benefits of simvastatin for TBI. • Simvastatin reduces TBI-induced ELOVL1 expression by inhibiting mTOR signaling. [ABSTRACT FROM AUTHOR]

T-cell death-associated gene 8 (TDAG8), a G-protein-coupled receptor sensing physiological or weak acids, regulates inflammatory responses. However, its role in traumatic brain injury (TBI) remains unknown. Our recent study showed that delayed CO 2 postconditioning (DCPC) has neuroreparative effects after TBI. We hypothesized that activating astrocytic TDAG8 is a key mechanism for DCPC. WT and TDAG8−/− mice received DCPC daily by transiently inhaling 10% CO 2 after controlled cortical impact (CCI). HBAAV2/9-GFAP-m-TDAG8-3xflag-EGFP was used to overexpress TDAG8 in astrocytes. The beam walking test, mNSS, immunofluorescence and Golgi-Cox staining were used to evaluate motor function, glial activation and dendritic plasticity. DCPC significantly improved motor function; increased total dendritic length, neuronal complexity and spine density; inhibited overactivation of astrocytes and microglia; and promoted the expression of astrocytic brain-derived neurotrophic factor in WT but not TDAG8−/− mice. Overexpressing TDAG8 in astrocytes surrounding the lesion in TDAG8−/− mice restored the beneficial effects of DCPC. Although the effects of DCPC on Days 14–28 were much weaker than those of DCPC on Days 3–28 in WT mice, these effects were further enhanced by overexpressing astrocytic TDAG8. Astrocytic TDAG8 is a key target of DCPC for TBI rehabilitation. Its overexpression is a strategy that broadens the therapeutic window and enhances the effects of DCPC. • Delayed CO 2 postconditioning (DCPC) improved motor function after CCI. • DCPC enhanced dendritic plasticity and inhibited astrocyte overactivation after CCI. • Astrocytic TDAG8 is a therapeutic target of DCPC for TBI rehabilitation. • TDAG8 overexpression broadened the therapeutic window of DCPC for TBI. [ABSTRACT FROM AUTHOR]

Stable unilateral vestibular deficit (vestibular neuronitis being the most common example in clinical practice) causes an imbalance in the information reaching the two vestibular nuclei at the level of the brain stem. This inequality of information arriving from the inner ear or the vestibular nerve is interpreted by the central vestibular structures as a rotation towards the ear from which it receives more information, generating the natural balancing reactions – nystagmus and vertigo, postural and walking imbalance. The physiological mechanism involved in the healing of such an injury is represented by the phenomenon of central vestibular compensation, an expression of the plasticity of the central vestibular structures. This natural recovery pattern begins in the first days after the acute injury and is a long-lasting process that allows good but incomplete recovery of dynamic deficits secondary to peripheral vestibular injury. This therapeutic window of the first week after onset should not be missed – initiation of pharmacological treatment (betahistine) from the first days and vestibular rehabilitation programs, both of which have been shown to facilitate and accelerate central vestibular compensation and ensuring maximum patient’s recovery [ABSTRACT FROM AUTHOR]

Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50–65% and 75–85% of the original dose for patients with a creatinine clearance (CrCL) of <30 ml/min and 30–60 ml/min, respectively. Tinzaparin should be adjusted to around 50% of the original dose for patients with a CrCL of <30 ml/min. In case anti-Xa monitoring is applied, trough concentration anti-Xa monitoring is preferred over peak monitoring, aiming at a maximum concentration of 0.4 IU/mL for once-daily dosed tinzaparin and 0.5 IU/mL for twice-daily dosed enoxaparin and nadroparin. [ABSTRACT FROM AUTHOR]

Emulgel is a promising drug delivery strategy that has gained popularity in recent years for topical delivery of hydrophobic drugs. Emulgel is an emulsion that is gelled by mixing it with gelling agents. It is an interesting topical drug delivery system as it has a dual release control system, i.e., gel and emulsion. Emulgel has several favorable properties for dermatological use such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, nonstaining, long shelf life, transparent and pleasing appearance. Despite, many advantages of the emulgel, the disadvantages include low permeability, poor pharmacokinetics and pharmacodynamics performance; therefore an advanced concept nanoemulgel came into the existence. Regardless of having few limitations, nanoemulgel formulation can be considered as impending and promising candidates for topical delivery of lipophilic drugs in the future. To know the potential of emulgel as a delivery vehicle, the present review offers a comprehensive overview on the rationale behind the use of emulgel, formulation considerations and characterization of emulgel and advanced research in the emulgel. Furthermore, we have summarized and discussed the outcome of different in vitro and in vivo studies of emulgel or nanoemulgel. Finally, the major challenges of nanoemulgel drug delivery system, patented and marketed emulgel or nanoemulgel formulations have been discussed. Based on the studies covered in this manuscript, it was understood that emulgel or nanoemulgel has emerged as an optimistic approach in the topical delivery of hydrophobic drugs to improve solubility, permeability and bioavailability, and reduce toxicities. [ABSTRACT FROM AUTHOR]

The article reflects the current achievements in the field of reperfusion therapy for ischemic stroke. The data are presented that allow a practicing neurologist to make informed decisions about intravenous thrombolysis in difficult clinical situations: minor stroke, suspected stroke "mask", atypical clinical picture, patient's age over 80 years, posterior circulation stroke, isolated dizziness, severe neurological deficit, large artery occlusion, chronic neuroimaging changes, polymorbidity and low functional level before stroke. It has been shown that an increase in the number of candidates for intravenous thrombolysis can be achieved by intensifying the selection of patients within the 4.5-hour therapeutic window, which primarily implies the optimization of local stroke treatment protocols with a reduction in the door-to-needle time, as well as, in the short term, expanding the therapeutic window. Approaches to reduce the risk of symptomatic hemorrhagic transformation are discussed. We are also talking about a rare but life-threatening complication angioedema. Thus, the intensification of intravenous thrombolysis, as well as an increase in its effectiveness and safety are the primary tasks of each stroke department.

Abstract Objective This study was aimed to determine how platelet reactivity (PR) on dual antiplatelet therapy predicts ischemic and bleeding events in patients underwent percutaneous coronary intervention (PCI). Design A total of 2768 patients who had received coronary stent implantation and had taken aspirin 100 mg in combination with clopidogrel 75 mg daily for > 5 days were consecutively screened and 1885 were enrolled. The recruited patients were followed-up for 12 months. The primary end-point was the net adverse clinical events (NACE) of cardiovascular death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and any bleeding. Result 1709 patients completed the clinical follow-up. By using the receiver operating characteristic (ROC) curve analysis, the optimal cut-off values were found to be 37.5 and 25.5% respectively in predicting ischemic and bleeding events. Patients were classified into 2 groups according to PR: inside the window group (IW) [adenosine diphosphate (ADP) induced platelet aggregation (PLADP) 25.5–37.4%)] and outside the window group (OW) (PLADP

English oral delivery of drug was the commonly used modality because of patient compliance and ease of administration. After oral administration of any drug, its bioavailability is affected by its residence time in stomach. Recently, gastroretentive drug delivery systems (GRDDS) have gained wide acceptance for drugs with a narrow absorption window, decreased stability at high alkaline pH, and increased solubility at low pH. This approach develops a drug delivery system, which gets retained within gastric fluid, thereby releasing its active principles in the stomach. Some methods used to achieve gastric retention of drugs include the use of effervescence agents, mucoadhesive polymers, magnetic material, bouncy enhancing excipient, and techniques that form plug-like devices that resist gastric emptying. This review provides a concise account of various attributes of recently developed approaches for GRDDS. [ABSTRACT FROM AUTHOR]

Microbial infection and insufficient tissue formation are considered to be the two main causes of dental implant failure. Novel studies have focused on designing dual-functional strategies to promote antibacterial properties and improve tissue cell response simultaneously. In this study, we investigated the antibacterial properties and cytocompatibility of silver nitrate (AgNO3) and strontium acetate (SrAc) in a mono-culture setup for dental application. Additionally, we defined the therapeutic window between the minimum inhibitory concentration against pathogenic bacteria and maximum cytocompatible dose in the case of combined applications in a co-culture setup. Antibacterial properties were screened using Aggregatibacter actinomycetemcomitans and cell response experiments were performed with osteoblastic cells (MC3T3) and fibroblastic cells (NIH3T3). The osteoinductive behavior was investigated separately on MC3T3 cells using alizarin red staining. A therapeutic window for AgNO3 as well as SrAc applications could be defined in the case of MC3T3 cells while the cytocompatibility of NIH3T3 cells was compromised for all concentrations with an antibacterial effect. However, the combined application of AgNO3/SrAc caused an enhanced antibacterial effect and opened a therapeutic window for both cell lines. Enhanced mineralization rates could be observed in cultures containing SrAc. In conclusion, we were able to demonstrate that adding SrAc to AgNO3 not only intensifies antibacterial properties but also exhibits bone inductive characteristics, thereby offering a promising strategy to combat peri-implantitis and at the same time improve osseointegration in implant therapy. [ABSTRACT FROM AUTHOR]

The main objective of this work was to demonstrate which kind of payload is the suitable choice for antibody–drug conjugates directed to widely expressed tumor-associated antigen. Trop-2 is overexpressed in various solid tumors, but it is also present on the epithelium of several normal tissues. A well-designed anti-Trop-2 ADC demands a good balance of efficacy and toxicity. In this research, MMAE, SN-38, and DXd were selected as candidates for payloads of the anti-Trop-2 mAb SY02. The antitumor activities and safety profiles of these ADCs were investigated to compare the therapeutic windows. Robust in vitro cytotoxicity was observed on human pancreatic cancer cell CFPAC-1 and breast cancer cell MDA-MB-468 with IC50 generally in the subnanomolar range. Consistent with in vitro assay, SY02-DXd and SY02-SN-38 demonstrated superior efficacy in CFPAC-1 xenograft models with TGI rates of 98.2% and 87.3%, respectively. However, SY02-MMAE could hardly inhibit the tumor growth. Subsequently, antitumor activities of these ADCs were further compared in MDA-MB-468 xenograft model. Complete tumor regression was observed in SY02-DXd and SY02-MMAE groups, indicating their potent antitumor activities. In an exploratory safety and pharmacokinetic study, SY02-DXd demonstrated the best safety profile with minimal adverse events in cynomolgus monkeys, while SY02-MMAE exhibited severe on-target skin toxicity which caused death. In conclusion, SY02-DXd demonstrated superior efficacy and safety with the widest therapeutic window. Based on the efficacy and safety results, moderate cytotoxic payloads would be ideal choices for ADCs targeting ubiquitously expressed antigens. [ABSTRACT FROM AUTHOR]

The increase in risk for acute ischemic stroke (AIS) with age is well established. If not treated properly and promptly, AIS can result in permanent neurological damage and even death. This literature review assesses the clinical outcomes of AIS patients treated with both intravenous thrombolysis (IVT) prior to mechanical thrombectomy (MT) compared to those treated solely with mechanical thrombectomy. Randomized controlled trials (RCTs) and meta-analyses published from 2015 to 2020 and available on PubMed were selected for review, and their quantitative and qualitative findings were extrapolated and summarized. Post-hoc analyses from ASTER and ETIS trials were reviewed as well as the impact of combined therapy and monotherapy on large vessel occlusions (LVO). Clinical outcomes in all examined trials demonstrated significant successful reperfusion as well as a higher rate of functional independence at 90 days for IVT prior to MT. Concerns of thrombus fragility, safety and cost effectiveness of dual therapy are also addressed. Based on these findings, we recommend the use of IVT as a pretreatment procedure to MT for AIS when eligible for IVT. Recent articles further strengthen this recommendation and provide new insights that IVT prior to MT is especially beneficial for patients presenting with multiple LVOs localized to the anterior intracranial circulation. Additional multi-center RCTs are necessary for further analysis of statistical outcomes demonstrating mixed effects. • Acute ischemic stroke can result in permanent neurological damage and even death. • Assesses the clinical outcomes of AIS patients. • Recommend the use of IVT as a pretreatment procedure to mechanical thrombectomy. [ABSTRACT FROM AUTHOR]

Objective: This study was aimed to determine how platelet reactivity (PR) on dual antiplatelet therapy predicts ischemic and bleeding events in patients underwent percutaneous coronary intervention (PCI). Design: A total of 2768 patients who had received coronary stent implantation and had taken aspirin 100 mg in combination with clopidogrel 75 mg daily for > 5 days were consecutively screened and 1885 were enrolled. The recruited patients were followed-up for 12 months. The primary end-point was the net adverse clinical events (NACE) of cardiovascular death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and any bleeding. Result: 1709 patients completed the clinical follow-up. By using the receiver operating characteristic (ROC) curve analysis, the optimal cut-off values were found to be 37.5 and 25.5% respectively in predicting ischemic and bleeding events. Patients were classified into 2 groups according to PR: inside the window group (IW) [adenosine diphosphate (ADP) induced platelet aggregation (PLADP) 25.5–37.4%)] and outside the window group (OW) (PLADP < 25.5% or ≥ 37.5%). The incidence of NACE was 16.8 and 23.1% respectively in the IW and OW group. The hazard ratio of NACE in IW group was significantly lower [0.69 (95% CI, 0.54–0.89, P = 0.004)] than that in the OW group during 12-month follow-up. Conclusion: An optimal therapeutic window of 25.5–37.4% for PLADP predicts the lowest risk of NACE, which could be referred for tailored antiplatelet treatment while using LTA assay. Trial registration: Trial registration number: ClinicalTrials.govNCT01968499. Registered 18 October 2013 - Retrospectively registered. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a severe cerebrovascular disease with high mortality and morbidity. In recent years, reperfusion treatments based on thrombolytic and thrombectomy are major managements for ischemic stroke patients, and the recanalization time window has been extended to over 24 h. However, with the extension of the time window, the risk of ischemia/reperfusion (I/R) injury following reperfusion therapy becomes a big challenge for patient outcomes. I/R injury leads to neuronal death due to the imbalance in metabolic supply and demand, which is usually related to mitochondrial dysfunction. Mitophagy is a type of selective autophagy referring to the process of specific autophagic elimination of damaged or dysfunctional mitochondria to prevent the generation of excessive reactive oxygen species (ROS) and the subsequent cell death. Recent advances have implicated the protective role of mitophagy in cerebral ischemia is mainly associated with its neuroprotective effects in I/R injury. This review discusses the involvement of mitochondria dynamics and mitophagy in the pathophysiology of ischemic stroke and I/R injury in particular, focusing on the therapeutic potential of mitophagy regulation and the possibility of using mitophagy-related interventions as an adjunctive approach for neuroprotective time window extension after ischemic stroke.

Ischemic stroke is a severe cerebrovascular disease with high mortality and morbidity. In recent years, reperfusion treatments based on thrombolytic and thrombectomy are major managements for ischemic stroke patients, and the recanalization time window has been extended to over 24 h. However, with the extension of the time window, the risk of ischemia/reperfusion (I/R) injury following reperfusion therapy becomes a big challenge for patient outcomes. I/R injury leads to neuronal death due to the imbalance in metabolic supply and demand, which is usually related to mitochondrial dysfunction. Mitophagy is a type of selective autophagy referring to the process of specific autophagic elimination of damaged or dysfunctional mitochondria to prevent the generation of excessive reactive oxygen species (ROS) and the subsequent cell death. Recent advances have implicated the protective role of mitophagy in cerebral ischemia is mainly associated with its neuroprotective effects in I/R injury. This review discusses the involvement of mitochondria dynamics and mitophagy in the pathophysiology of ischemic stroke and I/R injury in particular, focusing on the therapeutic potential of mitophagy regulation and the possibility of using mitophagy-related interventions as an adjunctive approach for neuroprotective time window extension after ischemic stroke. [ABSTRACT FROM AUTHOR]

Molecular photoswitches triggered with red or NIR light are optimal for photomodulation of complex biological systems, including efficient penetration of the human body for therapeutic purposes ("therapeutic window"). Yet, they are rarely reported, and even more rarely functional under aqueous conditions. In this work, fluorinated azobenzenes are shown to exhibit efficient E→Z photoisomerization with red light (PSS660nm >75 % Z) upon conjugation with unsaturated substituents. Initially demonstrated for aldehyde groups, this effect was also observed in a more complex structure by incorporating the chromophore into a cyclic dipeptide with propensity for self‐assembly. Under physiological conditions, the latter molecule formed a supramolecular material that reversibly changed its viscosity upon irradiation with red light. Our observation can lead to design of new photopharmacology agents or phototriggered materials for in vivo use. [ABSTRACT FROM AUTHOR]

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities. [ABSTRACT FROM AUTHOR]

Both high and low platelet responses to clopidogrel are highly associated with mortality. A therapeutic window for platelet reactivity was recently determined to be an important factor for improving clinical outcomes after percutaneous coronary intervention (PCI). We evaluated the impact of the antiplatelet activity of clopidogrel on long-term clinical outcomes in Korean patients receiving PCI. We analyzed the clinical outcomes of 814 Korean patients undergoing PCI for a median of 48 months. Platelet reactivity on clopidogrel was measured with the VerifyNow P2Y12 assay. The primary endpoint was all-cause death at 4 years. Patients were classified into three groups according to the P2Y12 reaction unit (PRU): low platelet reactivity (LPR; PRU < 85), normal platelet reactivity (NPR; 85 ≤ PRU < 208), and high platelet reactivity (HPR; PRU ≥ 208). The incidence of all-cause death was 7.0% in the LPR group, 1.5% in the NPR group, and 6.2% in the HPR group (log-rank p = 0.002). Based on multivariate analyses, all-cause death was significantly higher in both the LPR and HPR groups than in the NPR group (LPR, hazard ratio [HR]: 5.095; 95% confidence interval [95% CI]: 1.360–19.080, p = 0.016; HPR, HR: 3.315; 95% CI: 1.145–9.593, p = 0.027). Both LPR and HPR were significantly associated with long-term mortality in Korean patients receiving PCI, which suggests that the therapeutic concept of PRU may be an important prognostic factor.

Exposure to loud noise can cause hearing loss and tinnitus in mice and humans. In mice, one major underlying mechanism of noise-induced tinnitus is hyperactivity of auditory brainstem neurons, due at least in part, to decreased Kv7.2/3 (KCNQ2/3) potassium channel activity. In our previous studies, we used a reflex-based mouse model of tinnitus and showed that administration of a non-specific KCNQ channel activator, immediately after noise trauma, prevented the development of noise-induced tinnitus, assessed 1 week after trauma. Subsequently, we developed RL-81, a very potent and highly specific activator of KCNQ2/3 channels. Here, to test the timing window within which RL-81 prevents tinnitus in mice, we modified and employed an operant animal model of tinnitus, where mice are trained to move in response to sound but not move in silence. Mice with behavioral evidence of tinnitus are expected to move in silence. We validated this mouse model by testing the effect of salicylate, which is known to induce tinnitus. We found that transient administration of RL-81 1 week after noise exposure did not affect hearing loss but reduced significantly the percentage of mice with behavioral evidence of tinnitus, assessed 2 weeks after noise exposure. Our results indicate that RL-81 is a promising drug candidate for further development for the treatment of noise-induced tinnitus. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) are targeted therapeutic agents that treat cancers by selective delivery of highly potent cytotoxic drugs to tumor cells via cancer-specific antibodies. However, their clinical benefit is limited by off-target toxicity and narrow therapeutic windows. To overcome these limitations, we have applied reductive alkylation to develop a new type of ADC that has cytotoxic drugs conjugated to the N-terminal of an antibody through amine bonds introduced via reductive alkylation reactions (NTERM). To test whether the NTERM-conjugated ADCs can widen therapeutic windows, we synthesized three different ADCs by conjugating trastuzumab and monomethyl auristatin-F using three different methods, and compared their stability, efficacy, and toxicity. The NTERM-conjugated ADC was more stable in vitro and in vivo than the thiol-conjugated and the lysine-conjugated ADCs. The NTERM-conjugated ADC showed lower toxicity compared to other ADCs, whereas its efficacy was comparable to that of the thiol-conjugated ADC and better than that of the lysine-conjugated ADC. These results suggest that the NTERM conjugation method could widen the therapeutic window of ADCs by enhancing its stability and reducing toxicity.

T-cell engaging biologics is a class of novel and promising immune-oncology compounds that leverage the immune system to eradicate cancer. Here, we compared and contrasted a bispecific diabody-Fc format, which displays a relatively short antigen-binding arm distance, with our bispecific IgG platform. By generating diverse panels of antigen-expressing cells where B cell maturation antigen is either tethered to the cell membrane or located to the juxtamembrane region and masked by elongated structural spacer units, we presented a systematic approach to investigate the role of antigen epitope location and molecular formats in immunological synapse formation and cytotoxicity. We demonstrated that diabody-Fc is more potent for antigen epitopes located in the membrane distal region, while bispecific IgG is more efficient for membrane-proximal epitopes. Additionally, we explored other parameters, including receptor density, antigen-binding affinity, and kinetics. Our results show that molecular format and antigen epitope location, which jointly determine the intermembrane distance between target cells and T cells, allow decoupling of cytotoxicity and cytokine release, while antigen-binding affinities appear to be positively correlated with both readouts. Our work offers new insight that could potentially lead to a wider therapeutic window for T-cell engaging biologics in general.

Intravenous thrombolysis (IVT) represents the only systemic reperfusion therapy able to reverse neurological deficit in patients with acute ischemic stroke (AIS). Despite its effectiveness in patients with or without large vessel occlusion, it can be offered only to a minority of them, because of the short therapeutic window and additional contraindications derived from stringent but arbitrary inclusion and exclusion criteria used in landmark randomized controlled clinical trials. Many absolute or relative contraindications lead to disparities between the official drug label and guidelines or expert recommendations. Based on recent advances in neuroimaging and evidence from cohort studies, off-label use of IVT is increasingly incorporated into the daily practice of many stroke centers. They relate to extension of therapeutic time windows, and expansion of indications in co-existing conditions originally listed in exclusion criteria, such as use of alternative thrombolytic agents, pre-treatment with antiplatelets, anticoagulants or low molecular weight heparins. In this narrative review, we summarize recent randomized and real-world data on the safety and efficacy of off-label use of IVT for AIS. We also make some practical recommendations to stroke physicians regarding the off-label use of thrombolytic agents in complex and uncommon presentations of AIS or other conditions mimicking acute cerebral ischemia. Finally, we provide guidance on the risks and benefits of IVT in numerous AIS subgroups, where equipoise exists and guidelines and treatment practices vary. [ABSTRACT FROM AUTHOR]

Background: Only a small percentage of patients with acute stroke are currently eligible for thrombolysis, partly due to severe delays in hospital arrival. We had previously conducted the first regional study to assess the factors delaying acute stroke care in India. The present study aims to understand and describe in depth the variables associated with prehospital delay among patients admitted with an acute ischemic stroke., Methods: Data were prospectively collected by conducting an in-depth interview of 470 acute ischemic stroke patients and their bystanders, aged above 18 years, presenting to the Department of Emergency Medicine, Jubilee Mission Medical College and Research Institute, Thrissur. Patients who arrived within 4.5 h of symptom onset were considered as "early arrival" and those who arrived after 4.5 h were considered as "delayed arrival." Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation., Results: Of the 470 patients who met the inclusion criteria, 73 patients reached within 4.5 h (15.5%), whereas 397 patients arrived after 4.5 h. The mean age of acute stroke patients who reached within 4.5 h was 63 ± 13.7 years, whereas the mean age of those who reached after 4.5 h was 63 ± 12.1 years. Binary logistic regression performed to quantify the associations of prehospital factors showed an increased risk of prehospital delay among individuals with lack of awareness (odds ratio [OR] = 5.16 [3.040-8.757], P < 0.001), followed by those for whom a vehicle was not available at the site of event (OR = 3.745 [1.864-7.522], P < 0.001). Within the predefined socioeconomic strata, compared to lower class, upper middle class had less risk (OR = 0.135 [0.018-1.035], P = 0.054), whereas the distance from first medical contact to emergency department contributed moderate risk (OR = 1.071 [1.028-1.116], P < 0.001) for prehospital delay., Conclusions: Health promotion techniques that increase public knowledge about the early signs of stroke, transferring patients directly to hospitals with thrombolysis capabilities, and making ambulance services more widely available are appropriate measures to reduce prehospital delay., Competing Interests: SVA is a board member and RY is the co-chair of WSOTPC., (Copyright: © 2024 Annals of Indian Academy of Neurology.)

This perspective highlights the history and challenges of developing CD3-based bispecific T-cell engagers (TCEs) as cancer therapeutics as well as considerations and potential strategies for designing the next generation TCE molecules. The goal of this article is to raise awareness of natural T-cell biology and how to best harness the tumor cell killing capacity of cytotoxic T-cells with TCEs. In light of 30 years of concerted efforts to advance TCEs in early clinical development, many of the first-generation bispecific antibodies have exhibited lackluster safety, efficacy, and manufacturability profiles. As of January 2020, blinatumomab remains the only approved TCE. Many of the current set-backs in early clinical trials implicate the high-affinity CD3 binding domains employed and the respective bispecific platforms as potential culprits. The underlying conviction of the authors is that by taking corrective measures, TCEs can transform cancer therapy. Through openness, transparency, and much needed feedback from ongoing clinical studies, the field can continuously improve the design and effectiveness of next generation T-cell redirecting therapeutics.

Stroke is a threat to the health and life of the patient. Only early diagnosis and treatment in the so-called therapeutic window, enable effective help. This case represents an untreated 65-year-old man who suffered an acute stroke and was in a severe condition with full aphasia and hemiparesis transmitted by a medical emergency team in the emergency room of a hospital with a peripheral unit. Reliable intelligence at the scene, rapid transport to a dedicated treatment center, early imaging diagnostics and implemented thrombolytic therapy within 4.5 hours after the onset of symptoms, allowed to obtain a satisfactory final effect, despite co-existing cardiomyopathy.

Pharmaceutical drugs are an important part of the global healthcare system, with some estimates suggesting over 50% of the world's population takes at least one medication per day. Most drugs are delivered as immediate-release formulations that lead to a rapid increase in systemic drug concentration. Although these formulations have historically played an important role, they can be limited by poor patient compliance, adverse side effects, low bioavailability, or undesirable pharmacokinetics. Drug delivery systems featuring first-order release kinetics have been able to improve pharmacokinetics but are not ideal for drugs with short biological half-lives or small therapeutic windows. Zero-order drug delivery systems have the potential to overcome the issues facing immediate-release and first-order systems by releasing drug at a constant rate, thereby maintaining drug concentrations within the therapeutic window for an extended period of time. This release profile can be used to limit adverse side effects, reduce dosing frequency, and potentially improve patient compliance. This review covers strategies being employed to attain zero-order release or alter traditionally first-order release kinetics to achieve more consistent release before discussing opportunities for improving device performance based on emerging materials and fabrication methods. Unlabelled Image • A critical review of translational zero-order drug delivery systems. • Summary of the current state of common drug delivery devices. • Discussion of the techniques being employed to advance towards zero-order release. • Insight on the future of zero-order drug release. [ABSTRACT FROM AUTHOR]

The main purpose of this work was to construct an energy-dependent response curve of photobiomodulation on arterial pressure in hypertension animal model. To reach this objective, we have used a two-kidney one clip (2K-1C) rat model. Animals received acute laser light irradiation (660 nm) on abdominal region using different energy (0.6, 1.8, 3.6, 7.2, 13.8, 28.2, 55.8, and 111.6 J), the direct arterial pressure was measured by femoral cannulation, and systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR), and time of effect were obtained. Our results indicated that 660 nm laser light presents an energy-dependent hypotensive effect, and 28.2 J energy irradiation reached the maximum hypotensive effect, inducing a decreased SAP, DAP, and HR (decrease in SAP: - 19.23 ± 1.82 mmHg, n = 11; DAP: - 9.57 ± 2.23 mmHg, n = 11; HR: - 39.15 ± 5.10 bpm, n = 11; and time of hypotensive effect: 3068.00 ± 719.00 s, n = 11). The higher energy irradiation evaluated (111.6 J) did not induce a hypotensive effect and induced an increase in HR (21.69 ± 7.89 bpm, n = 7). Taken together, our results indicate that red laser energy irradiation from 7.2 to 55.8 J is the effective therapeutic window to reduce SAP, DAP, MAP, and HR and induce a long-lasting hypotensive effect in rats, with effect loss at higher energy irradiation (111.6 J). [ABSTRACT FROM AUTHOR]