Pozelimab, a human monoclonal immunoglobulin for the treatment of CHAPLE disease.

The complement is a crucial factor of the innate immune system. However, its activation can lead to various diseases, so it needs to be controlled. In mammals, surface-bound complement regulatory proteins safeguard cells from uncontrolled complement-mediated lysis. One of the human complement regulators is CD55, also known as the decay-accelerating factor (DAF), a single-chain, type I cell surface protein anchored to glycosylphosphatidylinositol (GPI). The genetic loss of the complement regulatory protein CD55 leads to a fatal illness known as CHAPLE disease. The complement and innate immunity become hyperactive in this disease, causing angiopathic thrombosis and protein-losing enteropathy. Patients with CHAPLE disease experience abdominal pain, nausea, vomiting, diarrhea, loss of appetite, weight loss, impaired growth, and swelling. This genetic condition has no known cure, and managing its symptoms can be challenging. Pozelimab, a human monoclonal immunoglobulin IgG4 antibody, is a drug that targets the terminal complement protein C5. The drug has a high affinity for both wild-type and variant human C5. Pozelimab has received designations such as fast track, orphan drug, and rare pediatric disease, making it a significant medical breakthrough. It is currently the only available treatment for this disease. In this review, we have summarized the preclinical and clinical data on pozelimab.

A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity.

BACKGROUND: Obesity is one of the critical public health problems in our society. It leads to various health conditions, such as type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. With the rising incidence of obesity, there is a growing demand for new therapies which can effectively manage body weight and improve health. CURRENT EVIDENCE: Currently under development, multi-receptor agonist drugs may offer a promising solution to meet this unmet medical need. Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). This novel drug has the potential to treat metabolic abnormalities associated with obesity as well as diseases resulting from it due to its distinct mechanism of action. The Phase III trial of this pipeline drug for treating type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity started on August 28, 2023. The results of a Phase II clinical trial have demonstrated significant weight reduction in overweight and obese adults. Specifically, the trial reported an average weight loss of 17.5% and 24.4% at 24 and 48 weeks, respectively. CONCLUSIONS: These findings hold promise for the development of effective weight loss interventions in this population group. There is a need for more phase III studies to provide sufficient clinical evidence for the effectiveness of retatrutide, as current evidence is limited to phase II studies and has yet to prove its worth in a larger population. Here, we aimed to provide an overview of retatrutide's safety and effectiveness in treating obesity.

Treatment Cost Along With Pattern of Disease and Therapy in the Intensive Care Unit of a Tertiary Care Teaching Hospital in India.

Background The intensive care unit (ICU) represents an important platform for conducting drug utilization analysis using defined daily dose (DDD)/100 bed-days and the financial burden of treatment as patients are seriously ill and are often suffering from chronic critical illnesses. Therefore, in this study, we evaluated the drug utilization patterns and cost of treatment in the ICU. Methods A retrospective observational analysis of the medical records obtained for the medical ICU of an apex tertiary care teaching hospital in central India was conducted for a period of three years from 2017 to 2019. All the patients admitted to the medical ICU during the study tenure were included in the study. Patients hospitalized in neonatal intensive care unit (NICU), pediatric intensive care unit (PICU), and surgical ICU were excluded from the study. The socio-demographic and clinical data, utilization of different classes of drugs, WHO-Anatomic Therapeutic Chemical (WHO-ATC) classification, DDD/100 bed days, hospital stay, etc. were analyzed. A partial pharmaco-economic analysis of the average cost of admission to patients was done. Results Data from 280 patients was assessed. The mean age was 47 ± 19.18 years and 58% were males. Antibiotics and injections were prescribed to 96% and 97.5% of the patients, respectively, during their ICU stay (median: seven days). Antimicrobial drugs were most frequently prescribed (n=1096, 68%); the most common were beta-lactams and carbapenems, followed by drugs acting on the central nervous system (5%) and cardiovascular system (4.3%). Cefoperazone/sulbactum, ceftriaxone, and piperacillin/tazobactam were the most utilized antibiotics with 8, 16, and 6 DDD/100 bed-days, respectively, while proton pump inhibitors, analgesics, and anti-epileptics were the most frequently prescribed non-antimicrobial drug class. The median cost of treatment per ICU admission was Indian Rupees (INR) 23,347 (IQR 12,552- 65,524). Conclusion Drug utilization assessment provides crucial information for understanding the usage of drugs in the settings of the ICU, and should be conducted regularly to help in the proper planning and implementation of rational drug use. Treatment costs reflect the high economic burden seen in ICU admissions.

Evidences and therapeutic advantages of donanemab in the treatment of early Alzheimer's disease.

The humanised monoclonal antibody donanemab is being developed to treat early onset Alzheimer's disease (AD). This drug targets N-truncated pyroglutamate amyloid-peptide at position 3 (N3pG), a modified form of deposited amyloid-peptide. The symptoms of Alzheimer's disease include gradual memory loss and other cognitive impairments. This disease is characterized by amyloid plaques, which are formed as a result of an accumulation of amyloid-(A-ß) peptides. Despite granting donanemab breakthrough therapy designation in June 2021, the FDA rejected donanemab's accelerated approval application in January 2023, due to inadequate safety data. According to the baseline amyloid level, the time to achieve plaque clearance (amyloid plaque level <24.1 centiloids) varied. Patients with higher baseline levels were more likely to achieve amyloid clearance. The safety of the drug was demonstrated by amyloid-related imaging abnormalities (ARIA), which ranged from 26.1 to 30.5 % in the studies. Clinical trial results have shown that donanemab delays cognitive and functional deterioration in patients with mild to moderate AD. However, it is not yet known whether donenameb offers therapeutic benefits that can change and improve the clinical condition of AD patients. To achieve significant clinical benefits in AD patients with cognitive impairment, further studies may be needed to investigate the interaction between A-ß plaque reduction and toxic tau levels.

Teplizumab: type 1 diabetes mellitus preventable?

Type 1 diabetes mellitus (T1DM) is an autoimmune condition driven by T lymphocytes that specifically declines the function of beta cells of pancreas. Immunological treatments aim to stop this decline in ß-cell function thus preventing TIDM. Although TIDM occur at any age, it is one of the most common chronic disorders in children. T1DM accounts for 5 to 10% of all cases of diabetes amounting 21-42 million affected persons. Teplizumab is a novel drug recently approved by the US FDA for the treatment of T1DM. This drug reduces abnormal glucose tolerance who are at high risk for developing T1DM and have antibodies suggesting an immunological attack on their pancreas. A 14-day infusion of the drug prevents T cells' attack of the insulin-producing cells of the pancreas. Adverse events due to teplizumab reported so far mild and of limited duration. This review gives an overview of the preclinical and clinical research on teplizumab for their role in new-onset T1DM.

Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2.

The COVID-19 pandemic remains a severe global threat, with the world engulfed in the struggle against the disease's second or third waves, which are approaching frightening proportions in terms of cases and mortality in many nations. Despite the critical need for effective therapy, there is still uncertainty about the optimal practices for treating COVID-19 with various pharmaceutical approaches. This being third year, global immunity and eradication of SARS-CoV-2 is currently seems to be out of reach. Efforts to produce safe and effective vaccinations have shown promise, and progress is being made. Additional therapeutic modalities, as well as vaccine testing in children, are required for prophylaxis and treatment of high-risk individuals. As a result, neutralising antibodies and other comparable therapeutic options offer a lot of promise as immediate and direct antiviral medications. Bispecific antibodies offer a lot of potential in COVID-19 treatment because of their qualities including stability, small size and ease of manufacture. These can be used to control the virus's infection of the lungs because they are available in an inhalational form. To combat the COVID-19 pandemic, innovative approaches with effective nanobodies, high-expression yield and acceptable costs may be required.

Antimicrobials in COVID-19: strategies for treating a COVID-19 pandemic.

The COVID-19 pandemic continues to pose a serious global challenge, with the world engulfed in fighting second, third and fourth waves of the disease, which is reaching scary proportions in terms of cases and mortality in countries like India. Despite the urgent need of proven management protocols, there is still confusion about the best practices for treating COVID-19 with different pharmaceutical interventions. Antimicrobials are empirically used in COVID-19 patients. During the initial phase of this pandemic, hydroxychloroquine, ivermectin, azithromycin and doxycycline were widely suggested for possible prophylaxis or treatment for COVID-19 in outpatient as well as hospitalized settings. Various national and international guidelines recommended its use. However, cumulative evidence from subsequent clinical trials has revealed no significant clinical benefits in any setting, with the risk of adverse effects being high particularly in combination with azithromycin. Yet, there is continued use of antimicrobials particularly in outpatient settings which should be avoided because there is no justifiable rationale for doing so. Antimicrobial resistance (AMR) was one of the top problems for global public health before the coronavirus 2019 (COVID-19) pandemic began. AMR, which is already a difficult problem, must now be handled in the context of a changing healthcare sector.

Clinical implications of anti-idiotype antibodies in COVID-19.

Idiotype-based therapeutics have failed to deliver their promise, necessitating rethinking of the concept and its potential to develop a viable immunotherapy method. The idiotype based hypothesis is discussed in this paper in order to produce effective anti-idiotype vaccinations. Polyclonal anti-idiotype reagents have been shown to be more successful in animal models, and a better understanding of the immune response in humans supports the idea that polyclonal anti-idiotype vaccines will be more effective than monoclonal-based anti-idiotype vaccines. This innovative approach can be used to produce therapeutic antibodies in a Biotech-standard manner. The idiotype network has been tweaked in the lab to provide protection against a variety of microbiological diseases. Antibodies to image-idiotype antigens, both internal and non-internal, can elicit unique immune responses to antigens. The current outbreak of severe acute respiratory syndrome 2 (SARS-2) has presented a fantastic chance to use idiotype/anti-idiotype antibodies as a protective regimen, which might be used to treat COVID-19 patients. The development of various effective vaccinations has been crucial in the pandemic's management, but their effectiveness has been limited. In certain healthy people, the development of viral variations and vaccinations can be linked to rare off-target or hazardous effects, such as allergic responses, myocarditis and immune-mediated thrombosis and thrombocytopenia. Many of these occurrences are most likely immune-mediated. The current analysis reveals successful idiotype/anti-idiotype antibody uses in a variety of viral illnesses, emphazising their importance in the COVID-19 pandemic.

An overview of post COVID sequelae.

After healing from COVID-19, patients often experience a slew of symptoms known as post COVID-19 sequelae. Despite the fact that the SARS-CoV-2 pandemic is still ongoing, post-Covid-19 syndrome is already a difficult problem to address: long-term multiorgan sequelae, while frequently described, have yet to be systematized. As a result, post-Covid-19 syndrome can have a major influence on surviving patients' working capacity as well as their personal lives. The clinical spectrum and long-term course of this clinical entity must be better understood. Post-Covid syndrome affects a wide spectrum of individuals (16-87%), with pneumological and cognitive symptoms being the most common. Pulmonary fibrosis was the most common organic consequence seen in post-Covid patients. In conclusion, post-Covid-19 syndrome can have a major impact on the health of survivors. Working-age patients should seek rehabilitation and follow-up in interdisciplinary rehabilitation programmes. Given the pandemic's global extent, it's obvious that COVID-19-related healthcare demands will continue to climb for the foreseeable future. For COVID-19 survivors' long-term mental and physical health, present outpatient infrastructure will be utilised, scalable healthcare models will be built, and cross-disciplinary collaboration will be required.

Antibody-dependent enhancement of virus infection and disease: implications in COVID-19.

Antibody-dependent enhancement (ADE) can be seen in a variety of viruses. It has a deleterious impact on antibody treatment of viral infection. This effect was first discovered in the dengue virus, and it has since been discovered in the coronavirus. Over 213 million people have been affected by the rapid spread of the newly emerging coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The new coronavirus offers a significant threat and has sparked widespread concern. ADE in dengue virus and other viruses are discussed with possible effect on COVID-19 treatment and vaccine development will need to consider this phenomenon to ensure it is mitigated and avoided altogether. In these case scenarios, the role of ADE and its clinical consequences remains to be explored for this newly detected virus.

Patterns of drug therapy, glycemic control, and predictors of escalation - non-escalation of treatment among diabetes outpatients at a tertiary care center.

OBJECTIVES: The study was conducted to assess patterns of prescribed drug therapy and clinical predictors of need for therapy escalation in outpatients with diabetes mellitus (DM). METHODS: This was a prospective cohort study, conducted at an apex tertiary care teaching hospital in central India for a period of 18 months. The demographic, clinical, and treatment details on the baseline and follow up visits were collected from the patients' prescription charts. Glycemic control, adherence, pill burdens along with pattern of antidiabetic therapy escalation, and deescalations were analyzed. RESULTS: A total of 1,711 prescriptions of 925 patients of diabetes with a mean age of 53.81 ± 10.42 years and duration of disease of 9.15 ± 6.3 years were analyzed. Approximately half of the patients (n=450) came for ≥1 follow up visits. Hypertension (59.35%) was the most common comorbidity followed by dyslipidemia and hypothyroidism. The mean total daily drugs and pills per prescription were 4.03 ± 1.71 and 4.17 ± 1.38, respectively. Metformin (30.42%) followed by sulphonylureas (SUs) (21.39%) constituted majority of the AHA's and dual and triple drug therapy regimens were most commonly prescribed. There were improvements in HbA1c, fasting/postprandial/random blood sugar (FBS/PPBS/RBS) as well as adherence to medication, diet, and exercise in the follow up visits. Among patients with follow ups, therapy escalations were found in 31.11% patients, among whom dose was increased in 12.44% and drug was added in 17.28%. Apart from Hb1Ac, FBS, and PPBS levels (p<0.001), characteristics such as age, BMI, duration of diagnosed diabetes, presence of hypertension and dyslipidemia, and daily pill burdens were found to be significantly higher in the therapy escalation group (p<0.05). Inadequate medication adherence increased the relative risk (RR) of therapy escalation by almost two times. CONCLUSIONS: Disease and therapy patterns are reflective of diabetes care as expected at a tertiary care center. Higher BMI, age, pill burden, duration of diabetes, presence of comorbidities, and poor medication adherence may be the predictors of therapy escalation independent of glycemic control and such patients should be more closely monitored.

Agreement between WHO-UMC causality scale and the Naranjo algorithm for causality assessment of adverse drug reactions.

BACKGROUND: The Pharmacovigilance Program of India recommends the use of the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale, while many clinicians prefer the Naranjo algorithm for its simplicity. In the present study, we assessed agreement between the two widely used causality assessment scales, that is, the WHO-UMC criteria and the Naranjo algorithm. MATERIALS AND METHODS: In this study, 842 individual case safety reports were randomly selected from 1000 spontaneously reported forms submitted to the ADR Monitoring Center at a tertiary healthcare Institute in Central India between 2016 and 2018. Two well-trained independent groups performed the causality assessment. One group performed a causality assessment of the 842 ADRs using the WHO-UMC criteria and the other group performed the same using the Naranjo algorithm. The agreement between two ADR causality scales was assessed using the weighted kappa (κ) test. RESULTS: Cohen's kappa coefficient (κ) statistical test was applied between the two scales (WHO-UMC scale and Naranjo algorithm) to find out the agreement between these two scales. "No" agreement was found between the two scales {Kappa statistic with 95% confidence interval = 0.048 (P < 0.001)}. CONCLUSION: There was no agreement found between the WHO-UMC criteria and the Naranjo algorithm in our study.

Optimal RNA binding by Egalitarian, a Dynein cargo adaptor, is critical for maintaining oocyte fate in Drosophila.

The Dynein motor is responsible for the localization of numerous mRNAs within Drosophila oocytes and embryos. The RNA binding protein, Egalitarian (Egl), is thought to link these various RNA cargoes with Dynein. Although numerous studies have shown that Egl is able to specifically associate with these RNAs, the nature of these interactions has remained elusive. Egl contains a central RNA binding domain that shares limited homology with an exonuclease, yet Egl binds to RNA without degrading it. Mutations have been identified within Egl that disrupt its association with its protein interaction partners, BicaudalD (BicD) and Dynein light chain (Dlc), but no mutants have been described that are specifically defective for RNA binding. In this report, we identified a series of positively charged residues within Egl that are required for RNA binding. Using corresponding RNA binding mutants, we demonstrate that specific RNA cargoes are more reliant on maximal Egl RNA biding activity for their correct localization in comparison to others. We also demonstrate that specification and maintenance of oocyte fate requires maximal Egl RNA binding activity. Even a subtle reduction in Egl's RNA binding activity completely disrupts this process. Our results show that efficient RNA localization at the earliest stages of oogenesis is required for specification of the oocyte and restriction of meiosis to a single cell.

A swine arterivirus deubiquitinase stabilizes two major envelope proteins and promotes production of viral progeny.

Arteriviruses are enveloped positive-strand RNA viruses that assemble and egress using the host cell's exocytic pathway. In previous studies, we demonstrated that most arteriviruses use a unique -2 ribosomal frameshifting mechanism to produce a C-terminally modified variant of their nonstructural protein 2 (nsp2). Like full-length nsp2, the N-terminal domain of this frameshift product, nsp2TF, contains a papain-like protease (PLP2) that has deubiquitinating (DUB) activity, in addition to its role in proteolytic processing of replicase polyproteins. In cells infected with porcine reproductive and respiratory syndrome virus (PRRSV), nsp2TF localizes to compartments of the exocytic pathway, specifically endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and Golgi complex. Here, we show that nsp2TF interacts with the two major viral envelope proteins, the GP5 glycoprotein and membrane (M) protein, which drive the key process of arterivirus assembly and budding. The PRRSV GP5 and M proteins were found to be poly-ubiquitinated, both in an expression system and in cells infected with an nsp2TF-deficient mutant virus. In contrast, ubiquitinated GP5 and M proteins did not accumulate in cells infected with the wild-type, nsp2TF-expressing virus. Further analysis implicated the DUB activity of the nsp2TF PLP2 domain in deconjugation of ubiquitin from GP5/M proteins, thus antagonizing proteasomal degradation of these key viral structural proteins. Our findings suggest that nsp2TF is targeted to the exocytic pathway to reduce proteasome-driven turnover of GP5/M proteins, thus promoting the formation of GP5-M dimers that are critical for arterivirus assembly.

Outpatient prescribing trends, rational use of medicine and impact of prescription audit with feedback at a tertiary care centre in India.

BACKGROUND: Rational use of medicines (RUM) is highly desired worldwide yet many shortcomings are found. This study aims to evaluate prescription pattern and RUM using World Health Organisation (WHO) prescribing indicators. The impact of audit and feedback has also been studied, along with comparison with published data. METHODS: A cross-sectional observational study was conducted in the outpatient department setting of a tertiary care centre in central India. Data were collected from 2719 prescriptions across different departments from hospital pharmacies from 2016 to 2018 at different time periods. The data was analysed using WHO core prescribing indicators. RESULTS: Average number of drugs per prescription was found to be 2.53 ± 1.23 (WHO optimal value ≤ 2). The mean values of prescribing indicators for antibiotics (19.82% vs. ≤ 30%) and injection prescribing (1.98% vs. ≤10%) were within optimal values. Generic prescribing (15.96% vs. 100%) and prescribing from National List of Essential Medicines (NLEM; 37.37% vs. 100%) were found to be significantly lesser. Annual audit and feedback showed improvement in generic prescribing and prescribing from NLEM, but the other trends continued to be similar. CONCLUSION: While use of antibiotics and injections among outpatients was found to be rational, there is scope of improvement in most domains that can be addressed with appropriate interventions.

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase.

Soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO); sGC thereby acts as an amplifier in NO-driven biological signaling cascades. Because sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production, boosting sGC activity and preventing or reversing sGC inactivation are important therapeutic and pharmacologic goals. Work over the last two decades is uncovering the processes by which sGC matures to become functional, how sGC is inactivated, and how sGC is rescued from damage. A diverse group of small molecules and proteins have been implicated in these processes, including NO itself, reactive oxygen species, cellular heme, cell chaperone Hsp90, and various redox enzymes as well as pharmacologic sGC agonists. This review highlights their participation and provides an update on the processes that enable sGC maturation, drive its inactivation, or assist in its recovery in various settings within the cell, in hopes of reaching a better understanding of how sGC function is regulated in health and disease.

Alternative splicing of the metalloprotease ADAMTS17 spacer regulates secretion and modulates autoproteolytic activity.

ADAMTS proteases mediate biosynthesis and breakdown of secreted extracellular matrix (ECM) molecules in numerous physiological and disease processes. In addition to their catalytic domains, ADAMTS proteases contain ancillary domains, which mediate substrate recognition and ECM binding and confer distinctive properties and roles to individual ADAMTS proteases. Although alternative splicing can greatly expand the structural and functional diversity of ADAMTS proteases, it has been infrequently reported and functional consequences have been rarely investigated. Here, we characterize the structural and functional impact of alternative splicing of ADAMTS17, mutations in which cause Weill-Marchesani syndrome 4. Two novel ADAMTS17 splice variants, ADAMTS17A and ADAMTS17B, were investigated by structural modeling, mass spectrometry, and biochemical approaches. Our results identify a novel disulfide-bridged insertion in the ADAMTS17A spacer that originates from inclusion of a novel exon. This insertion results in differential autoproteolysis of ADAMTS17, and thus, predicts altered proteolytic activity against other substrates. The second variant, ADAMTS17B, results from an in-frame exon deletion and prevents ADAMTS17B secretion. Thus, alternative splicing of the ADAMTS spacer significantly regulates the physiologically relevant proteolytic activity of ADAMTS17, either by altering proteolytic specificity (ADAMTS17A) or by altering cellular localization (ADAMTS17B).