Future Pharmacol., Volume 3, Issue 2 (June 2023) – 12 articles

IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and is one of the most common causes of end-stage kidney disease (ESKD) worldwide. The immunopathogenic mechanism underlying IgAN is poorly identified. Currently, the mainstay treatment of IgAN is centered on the optimization of blood pressure and a reduction in proteinuria, using an angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs). According to KDIGO, patients who persistently remain at a high risk of progressive ESKD, despite maximal supportive care, are candidates for glucocorticoid therapy. Recent discoveries regarding the pathogenesis of this disease have led to the testing of new therapeutic drugs targeting, in particular, the excessive mucosal immune reaction and the resulting systemic response as well as the complement activation and the following kidney damage and fibrosis. In this review, we examine the various therapeutic approaches to this intriguing disease. Full article

Endometrial cancer (EC) and cervical cancer (CC) are common malignancies in women in clinical practice. More uncommon non-ovarian malignancies, such as vulval cancer (VC), are also becoming more prevalent in women of all ages. Currently, there are few comprehensive reviews on the management of these conditions, despite the recent advances in the use of immunotherapy in the management of other forms of cancer. The treatment modalities for EC, CC and VC vary; however, platinum-based chemotherapy, surgical resection and radiotherapy are the main forms of treatment. In more advanced or recurrent disease, there is a limited number of efficacious treatments, with many clinicians relying on adjuvant chemotherapy despite the increased rationale for the use of immunotherapy. With the development of the novel adoptive T-cell therapy, intra-tumoural oncolytic viral therapy and cancer vaccines, the landscape of gynaecological cancer management is changing, and it is likely that treatment efficacy and outcomes will improve dramatically. This review aims to summarise the current management of endometrial, cervical and vulval cancer and to evaluate the novel therapies under development, as well as the future of the management of non-ovarian gynaecological malignancies. Full article

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a worldwide non-fermenting Gram-negative bacillus responsible for potentially severe nosocomial infections, especially in critically ill patients. CRAB tends to colonize inert surfaces and epithelia, especially the respiratory tract of mechanically ventilated patients, and may then become responsible for lower respiratory tract infections, probably the more challenging infection due to the site and the multidrug-resistant phenotype which makes it difficult to establish an effective antimicrobial regimen. Despite its diffusion, data regarding the treatment of CRAB are mainly retrospective and usually heterogeneous. Current international consensus guidelines prefer the use of ampicillin/sulbactam, but the strength of recommendation and grade of evidence tend to be weak to moderate. Moreover, no specific recommendation is given for different sites of infections. The recently introduced cefiderocol still received a recommendation against its use due to the results of the first randomized clinical trial, though retrospective and observational experiences showed favourable outcomes in this setting. We reviewed the major antibacterial drugs active against CRAB and discussed their combination in lower respiratory tract infections. Full article

In this study, we retrospectively reviewed the outcomes of patients treated with one or more series of intravitreal methotrexate (MTX) injections as a surgical adjunct for the prevention of recurrent rhegmatogenous retinal detachment (RRD) related to proliferative vitreoretinopathy (PVR). The study subjects were patients with primary or recurrent RRD associated with grade C PVR, who received one or more series of 9 intravitreal MTX injections. Each series consisted of a single intraoperative MTX injection and then 8 weekly postoperative MTX injections as an off-label surgical adjunct for the prevention of PVR. The primary outcome was the retinal reattachment rate. The secondary outcome was the incidence of treatment-limiting side effects. A total of 14 eyes of 14 patients were identified. The median age was 61 years (range: 9–83), and 43% of the patients were female. Most patients (64%) had a prior primary surgical failure. After one MTX series, 10 eyes (72%) were attached, and 8 (57%) were free of PVR at a median follow-up of 11 months (range: 2–14). All failures after a single MTX series were successfully treated with repeat surgery and a second (n = 4) or third (n = 1) MTX series, for the final reattachment and PVR-free rates of 100%. None of the patients experienced treatment-limiting side effects. Therefore, multiple series of MTX injections can be tolerated if indicated in cases of aggressive PVR threatening the retina. Full article

Curcumin is a biopharmaceutical classification system (BCS) class IV substance with many potential therapeutic effects. However, like many other BCS IV active pharmaceutical ingredients, complex formulations are needed to guarantee a sufficiently high bioavailability. A not-so-well-known delivery system is a suspoemulsion (SE). SEs are emulsions with a crystalline API in continuous or dispersed phases. This study aimed to produce curcumin-loaded o/w suspoemulsions with the particle in the oil phase for, e.g., encapsulation or triggered release effects. The particles need to be smaller than the emulsion droplet size to attain high encapsulation efficiencies (EE) in the oil phase. Sonofragmentation and bead milling were tested for their ability to produce these nanocrystals in different dispersion media. It was discovered that production in miglyol was the best fit for the needed application of the crystals in SEs. Around 85% (by volume) of the particles produced with bead milling were smaller than the droplet size of about 5 µm. In contrast, only 23% of the sonofragmentated particles were below the diameter of those droplets. This oily suspension was then used to successfully produce hydrogel-based o/w suspoemulsions. In the second part of this study, we investigated different methods for determining encapsulation efficiency, but none of the methods accurately and satisfactorily resolved the encapsulation efficiency. Finally, the suspoemulsions could not be macroscopically distinguished from one another and were physically stable. In summary, we showed that stable hydrogel-based curcumin-loaded o/w suspoemulsions could be produced. Full article

Fetal arrhythmias complicate 1% of pregnancies. Although most of them have a benign and intermittent course, sustained fetal tachyarrhythmias constitute an emerging situation, which is associated with high fetal morbidity and mortality. However, one of the major milestones in fetal therapy is the pharmacologic management of fetal arrhythmias by crossing the placental barrier. To date, there is no consensus on the first-line antiarrhythmic treatment for fetal tachyarrhythmias. The role of sotalol in therapeutic management, the use of flecainide versus digoxin as first line of treatment, the need for fetal intramuscular treatment administration, or the best treatment in case of fetal hydrops are situations whose application or management are controversial. The current paper is a scoping review of observational and experimental evidence, addressing the types of best management strategies for each type of tachyarrhythmia and the optimal pharmacological dose, considering precautions and safety elements. Finally, we will highlight new therapeutic perspectives and future diagnostic and therapeutic strategies. Full article

To evaluate possible structural changes and thermal stability of the polyurea unloaded and loaded with diclofenac sodium, polyurea networks based on polyetheramine containing polypropylene oxide (PPO) or polyethylene oxide (PEO) and hexamethylene diisocyanate trimer-HDI were synthesized. The formation of the network was controlled by sol-gel reactions, and the obtained materials were then characterized by different techniques (FTIR, XRD, TGA). Moreover, the amount of diclofenac released could be modulated as a function of time, studying the water absorption or swelling capacity, the cytotoxicity of the material and the amount of drug released. A choice was therefore made on the hydrophilicity of PEO- or PPO-based polyetheramine (with similar molecular weight), and the release profile was hereafter correlated with the water absorption by the PEO/PPO polyurea matrix. Links could finally be established between the release of diclofenac and the polyurea matrices properties, such as the nature of polymer (PEO/PPO) and the hydrophilicity (water uptake). Our objective here is to identify challenges and opportunities for the development of innovative functional biomaterials for health applications. Full article

Depression is a neuropsychiatric disorder characterized by altered emotion and cognition. Alpha lipoic acid (ALA) is a potent natural antioxidant and exhibits neuroprotective effects. However, its antidepressant activity and its mechanism of action in rats exposed to chronic unpredictable mild stress (CUMS) need to be evaluated. The rats were divided into six groups. Group, I vehicle control (without stress), II- CUMS, III- fluoxetine (FLX) (50 mg/kg p.o.), IV, V, and VI were treated with ALA (50, 100, 200 mg/kg, p.o.), respectively. All the groups, except I, were subjected to CUMS + treatments from day 1 to day 42. Body weight and behavioral parameters like sucrose preference test (SPT), Morris water maze (MWM), resident intruder test (RIT), and marble-burying test (MBT) were performed on day 0, day 21, and day 42, and forced swim test (FST) on last day 42 and 43 only. The rats were further sacrificed for biochemical and histopathological evaluation. ALA significantly improved behavioral function, increased antioxidant strength, reduced lipid peroxidation, restored monoamines, and protected CA3 neurons. Further, docking studies revealed strong binding of ALA on the 5HT₃ receptor. The study demonstrates that ALA might be exhibiting antidepressant effects in part by restoring monoamines and modulating the 5HT₃ receptor. Full article

The goal in cardiovascular prevention is the reduction of morbidity and mortality through the promotion of healthy lifestyles in the general population. The management of modifiable risk factors with pharmacological and non-pharmacological interventions, based on the individual risk is the first strategy suggested by the current guidelines. Several epidemiological studies have clearly shown the direct correlation between high levels of low-density lipoprotein cholesterol (LDL-C) and incidence of cardiovascular diseases. On the other hand, numerous randomized clinical studies have reported a huge benefit in terms of major cardiovascular events achievable by the reduction of LDL-C, thus supporting the notion that “the lower is better”. Among the lipid-lowering strategies, statins are the drugs of choice in cardiovascular prevention, at both primary and secondary level. To achieve the ambitious targets suggested by the current guidelines, other lipid-lowering therapies are currently available in addition to statins, such as ezetimibe the inhibitors of the PCSK9. Pharmacological research has recently led to the development of a new drug, the bempedoic acid, which further enrich the available therapies. This drug also acts on the biosynthesis of cholesterol but at upstream level than statins. From the biochemical point of view, it has the potential to be considered before the statin with consequent titration of statins to achieve the desirable LDL-C target. In the present review, the biochemical and pharmacological characteristics of bempedoic acid are discussed. An overview of the clinical data that support its use in the management of the cardiovascular patient and its allocation in the lipid-lowering scenario will be also provided. Full article

The enoyl reductase from Mycobacterium tuberculosis (MtInhA) was shown to be a major target for isoniazid, the most prescribed first-line anti-tuberculosis agent. The MtInhA (EC 1.3.1.9) protein catalyzes the hydride transfer from the 4S hydrogen of β-NADH to carbon-3 of long-chain 2-trans-enoyl thioester substrates (enoyl-ACP or enoyl-CoA) to yield NAD⁺ and acyl-ACP or acyl-CoA products. The latter are the long carbon chains of the meromycolate branch of mycolic acids, which are high-molecular-weight α-alkyl, β-hydroxy fatty acids of the mycobacterial cell wall. Here, stopped-flow measurements under single-turnover experimental conditions are presented for the study of the transient of reactants. Single-turnover experiments at various enzyme active sites were carried out. These studies suggested isomerization of the MtInhA:NADH binary complex in pre-incubation and positive cooperativity that depends on the number of enzyme active sites occupied by the 2-trans-dodecenoyl-CoA (DD-CoA) substrate. Stopped-flow results for burst analysis indicate that product release does not contribute to the rate-limiting step of the MtInhA-catalyzed chemical reaction. The bearings that the results presented herein have on function-based anti-tuberculosis drug design are discussed. Full article

Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections. Full article