Zydus Lifesciences bags USFDA nod for HIV-1 drug Darunavir

Ahmedabad: Zydus Lifesciences Limited today announced that the Company has received final approval from the United States Food and Drug Administration
(USFDA) for Darunavir Tablets 600 mg and 800 mg, and tentative approval for 75 mg and 150
mg tablets (USRLD: Prezista Tablets, 75 mg, 150 mg, 600 mg, and 800 mg).

Darunavir is a protease inhibitor antiviral medicine that prevents Human Immunodeficiency
Virus (HIV-1) from multiplying in the body. It is indicated for the treatment of HIV-1 infection
in adult patients. It is also indicated for the treatment of HIV-1 infection in pediatric patients 3
years of age and older.

It must be –co-administered with Ritonavir and with other antiretroviral
agents.

The product will be manufactured at the group’s formulation manufacturing facility in
SEZ, Ahmedabad (India).

Darunavir Tablets, 75 mg, 150 mg, 600 mg, and 800 mg had annual sales of USD 275 mn in
the United States (IQVIA MAT Oct. 2023).
The group now has 383 approvals and has so far filed over 440* ANDAs since the
commencement of the filing process in FY 2003-04.

Read also: Zydus, Daewoong Pharma collaborate to co-develop, commercialise Leuprolide Long-Acting Injectable in US

Formerly known as Cadila Healthcare Limited, Zydus Lifesciences Limited is an Indian multinational pharmaceutical company headquartered in Ahmedabad. The company is primarily engaged in the production of generic drugs. Cadila was founded in 1952 by Ramanbhai Patel.

Read also: Zydus Lifesciences gets USFDA okay for acquired methemoglobinemia injection Methylene Blue

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Synthetic Glucocorticoids use tied to Neuropsychiatric Effects, depression and mania most common

A recent systematic review and meta-analysis shed light on the neuropsychiatric effects of synthetic glucocorticoids, commonly used in treating various diseases. Glucocorticoids, known for their efficacy, are associated with neuropsychiatric adverse effects, prompting researchers to delve into their prevalence and severity. This study was published in The Journal Of Clinical Endocrinology & Metabolism by Anne-Sophie C A M Koning and colleagues.

The comprehensive analysis involved 49 studies, encompassing various patient populations, types, doses, and durations of synthetic glucocorticoid use. Here are the significant findings regarding neuropsychiatric adverse effects among glucocorticoid users:

  • Depression (22%): The proportion of patients experiencing depression following glucocorticoid use was reported at 22% (95%CI 14%-33%).
  • Mania (11%): Neuropsychiatric effects extended to mania, with an 11% prevalence (95%CI 2%-46%) observed among users.
  • Anxiety (8%): Approximately 8% of patients reported anxiety (95%CI 2%-25%) as an adverse effect.
  • Delirium (16%): Delirium was noted in 16% of cases (95%CI 6%-36%).
  • Behavioural Changes (52%): A substantial 52% of users reported experiencing behavioural changes (95%CI 42%-61%).

Psychiatric Scores:

Further analysis evaluated questionnaire scores between glucocorticoid users and non-users:

  • Depression (SMD 0.80): Glucocorticoid users showed higher scores for depression (SMD of 0.80 (95%CI 0.35-1.26)), suggesting a greater incidence of depressive symptoms.
  • Mania (SMD 0.78): Similarly, mania scores were elevated in users (SMD of 0.78 (95%CI 0.14-1.42)), indicating increased manic symptoms post glucocorticoid use.

The study underscores the substantial neuropsychiatric adverse effects associated with synthetic glucocorticoid use. Notably, depression and mania demonstrated the most pronounced associations with glucocorticoid treatment. Researchers emphasize the critical need for awareness among healthcare professionals and patients regarding the potential neuropsychiatric side effects upon initiating glucocorticoid therapy. The findings highlight the necessity for more structured investigations into the incidence and underlying pathways of these adverse effects.

Reference:

Koning, A.-S. C. A. M., van der Meulen, M., Schaap, D., Satoer, D. D., Vinkers, C. H., van Rossum, E. F. C., van Furth, W. R., Pereira, A. M., Meijer, O. C., & Dekkers, O. M. Neuropsychiatric adverse effects of synthetic glucocorticoids: a systematic review and meta-analysis. The Journal of Clinical Endocrinology and Metabolism,2023. https://doi.org/10.1210/clinem/dgad701

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Bestatin promising drug for treatment and prevention of periodontitis

Researchers have found in a new study that Bestatin may be a promising drug for treatment and prevention of periodontitis.  The findings of the  new study have been published in the Journal of Periodontology.

Chronic periodontitis (CP), the most prevalent dysbiotic bacteria-driven chronic inflammatory disease, is an underestimated global health problem in itself, and due to a causative relationship with other disorders such as cardiovascular diseases or Alzheimer disease. The Chronic periodontitis pathogenesis is primarily driven by Porphyromonas gingivalis in humans, and Porphyromonas gulae in dogs. These microorganisms initiate a pathogenic shift in the composition of the tooth-surface microflora. The objective of researchers was to evaluate antimicrobial effects of bestatin, a potential Chronic periodontitis drug candidate.

Researchers evaluated bestatin bacteriostatic efficiency against periodontopathogens in planktonic cultures via microplate assay, and mono- and multispecies oral biofilm models. Neutrophil bactericidal activities, such as phagocytosis, were investigated in vitro using granulocytes isolated from the peripheral blood. The therapeutic efficacy and the immunomodulatory function of bestatin was assessed in a murine model of Chronic periodontitis.

Results

Bestatin exhibited bacteriostatic activity against both P. gingivalis and P. gulae, and controlled the formation and species composition of the biofilm. We demonstrated that bestatin promotes the phagocytosis of periodontopathogens by neutrophils. Finally, we found that providing bestatin in the animal feed prevented alveolar bone resorption.

They showed that in a murine model of Chronic periodontitis bestatin not only shifted the biofilm species composition from pathogenic to a commensal one, but also promoted bacteria clearance by immune cells and alleviated inflammation. Taken together, these results suggest that bestatin is a promising drug choice for the treatment and/or prevention of periodontitis and clinical trials are required to fully evaluate its potency.

Reference:

Kaminska, M, Benedyk-Machaczka, M, Adamowicz, K, et al. Bestatin as a treatment modality in experimental periodontitis. J Periodontol. 2023; 94: 1338–1350. https://doi.org/10.1002/JPER.22-0614

Keywords:

Bestatin, promising, drug, for, treatment, prevention, periodontitis, Kaminska, M, Benedyk-Machaczka, M, Adamowicz, K

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Use of diffusion optics technology spectacle lenses may prevent juvenile myopia progression

Researchers have found in a new study that Use of diffusion optics technology spectacle lenses may prevent juvenile myopia progression. 

The findings of the new study have been published in the British Journal of Ophthalmology.

Mutations in the L/M cone opsin gene array cause abnormally high perceived retinal contrast and the development of myopia. Environmental factors may also lead to high visual contrast and cause myopia. Diffusion optics technology (DOT) lenses are designed to reduce contrast signalling in the retina and slow myopia progression.

The Control of Myopia Using Peripheral Diffusion Lenses Efficacy and Safety Study (CYPRESS, NCT03623074) is a 36-month, multicentre, randomised, controlled, double-masked trial evaluating two investigational spectacle lenses versus control lenses in myopic children aged 6–10, with a planned interim analysis at 12 months. The primary endpoints are change from baseline in axial length (AL) and spherical equivalent refraction (SER).

Results

In all 256 children (58% female; mean age at screening, 8.1 years) were dispensed spectacles. Across all groups, baseline averages were AL 24.02 mm (SD±0.77 mm), SER −2.01 D (SD±0.9 D) using manifest refraction, and SER −1.94 D (SD±1.0 D) using cycloplegic autorefraction. At 12 months, mean difference in SER progression for test 1 versus control was −0.40 D (p<0.0001), representing a 74% reduction and −0.32 D for Test 2 (p<0.0001), representing a 59% reduction. The difference in AL progression for test 1 versus control was 0.15 mm (p<0.0001) and test 2 versus control was 0.10 mm (p=0.0018).

Reseachers concluded that 12-month results from this ongoing trial demonstrate the safety and effectiveness of Diffusion optics technology (DOT) spectacles for reducing myopic progression.

Reference:

Rappon J, Chung C, Young G, et alControl of myopia using diffusion optics spectacle lenses: 12-month results of a randomised controlled, efficacy and safety study (CYPRESS) British Journal of Ophthalmology 2023;107:1709-1715.

Keywords:

Use, diffusion, optics, technology, spectacle, lenses, may, prevent, juvenile, myopia, progression, British Journal of Ophthalmology

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Valproate Use Linked to Brain Volume Reduction in Epilepsy Patients

Recent study unveiled important findings about the impact of valproate (VPA) use on the brain volume of individuals with idiopathic generalized epilepsy. The crucial results of the extensive study were published in Epilepsia Journal.

The study employed voxel-based morphometry on magnetic resonance imaging (MRI) and focused on 112 patients currently using VPA (VPA+ group), 81 not using VPA (VPA– group), and 120 healthy subjects for comparison.

The findings indicated significant gray matter (GM) volume reduction in the VPA+ group in various brain regions, including the bilateral cerebellum, hippocampus, insula, caudate nucleus, medial frontal cortex/anterior cingulate cortex, primary motor/premotor cortex, medial occipital cortex, and anteromedial thalamus. When compared to the control group, the VPA– group also exhibited GM volume reduction in the anteromedial thalamus and right hippocampus/temporal cortex.

The study found distinctive differences the VPA+ group, when compared to the VPA– group which showed more extensive GM volume reduction in the bilateral cerebellum, primary motor/premotor cortex, and medial frontal cortex/anterior cingulate cortex.

These findings found the potential adverse effects of VPA on brain structure, particularly in the frontal cortex and cerebellum. The study suggests that the use of VPA may contribute to cortical thinning and GM volume reduction, urging caution while interpreting morphometric MRI studies involving individuals taking VPA.

The study emphasizes the importance of considering VPA use as a potential confounding factor in studies exploring brain morphometry. Understanding these associations is crucial not only for clinicians prescribing VPA but also for researchers aiming to accurately interpret MRI data in epilepsy studies. Further investigations are imperative to validate the clinical implications and long-term effects of these structural changes that were observed in epilepsy patients using VPA.

Source:

Shin, J. H., Song, M. J., & Kim, J. H. (2023). Valproate use associated with frontal and cerebellar gray matter volume reductions: A voxel‐based morphometry study. In Epilepsia. Wiley. https://doi.org/10.1111/epi.17825

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Point-of-care PCR may help guide antibiotic choice and improve pneumonia treatment

Community-acquired pneumonia (CAP) is a leading cause of hospitalization and death. Timely antibiotic treatment is crucial to prevent complications like bacteremia, sepsis, organ failure, and death. Initial treatment is often empiric, and an uncertain or delayed diagnosis can lead to broad-spectrum antibiotic use. This contributes to adverse effects, such as Clostridioides difficile infection and super-infections with resistant bacteria, and can worsen patient outcomes and contribute to antibiotic resistance.

A study published in PLOS ONE has concluded that using respiratory POC does not appear to be effective in reducing antibiotic use in a setting with low antimicrobial resistance and already prudent antibiotic use. However, it may help ensure targeted and appropriate treatment in a restrictive antibiotic setting and support a restrictive strategy. The COVID-19 pandemic and low transmission of common respiratory viruses during the study period may have impacted the results.

We need rapid and accurate detection of pathogens in community-acquired pneumonia (CAP) to use appropriate antibiotics and slow down antibiotic resistance development. The study aimed to compare the effect of adding point-of-care (POC) polymerase chain reaction (PCR) detection of respiratory pathogens to standard care with standard care only (SCO) on antibiotic prescriptions after acute hospital admission.

They conducted an open-label, multicenter, parallel-group, superiority RCT at three Danish medical emergency departments from March 2021 to February 2022. Adults with suspected CAP during daytime weekdays were included and randomly assigned (1:1) to POC-PCR or SCO analysis of respiratory samples. Two hundred ninety-four patients with collected samples were randomly assigned to POC-PCR (n = 148, 50.4%) or SCO (n = 146, 49.6%). The study used logistic regression and Huber–White clustered standard errors for the prescription of antibiotic treatment. The study included intention-to-treat and per-protocol analysis.

Key findings from the study are:

  • Loss to follow-up comprises three patients in the POC-PCR and none in the SCO group.
  • There was no difference in the primary outcome of prescriptions of no or narrow-spectrum antibiotics four hours after admission for the POC-PCR and SCO.
  • The prescriptions were more targeted at four h (OR 5.68) and 48 h (OR 4.20)and more adequate at 48 h (OR 2.11) and on day 5 in the POC-PCR group (OR 1.40).
  • There was no difference between the groups about intensive care unit (ICU) admissions, readmission within 30 days, length of stay, 30-day mortality and in-hospital mortality.

· The POC-group patients showed a non-statistically significant shortening of hospital stay by approximately one day.

· The POC group treated more patients with targeted antibiotics within 48 hours and five days after admission.

Antimicrobial resistance is low in Denmark, and most Haemophilus influenzae and Streptococcus pneumoniae are susceptible to benzylpenicillin. Danish guidelines recommend narrow-spectrum penicillin for milder CAP cases and broad-spectrum antibiotics for severe cases. CAP diagnosis is based on clinical symptoms and unspecific diagnostic tools like auscultation, chest radiography, blood tests, and microbiological analysis of sputum samples.

They said that in a setting with limited antibiotic use, point-of-care – polymerase chain reaction (POC-PCR) did not increase the number of patients treated with narrow-spectrum or without antibiotics. However, it showed potential for more targeted and appropriate antibiotic use. A study limitation was the COVID-19 pandemic, which led to low respiratory virus transmission.

Reference:

: Cartuliares MB et al. Evaluation of point-of-care multiplex polymerase chain reaction in guiding antibiotic treatment of patients acutely admitted with suspected community-acquired pneumonia in Denmark: A multicentre randomized controlled trial. PLoS Med 20(11): e1004314. https://doi.org/10.1371/journal.pmed.1004314

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Statin Initiation Linked to Reduced Mortality in Chronic Kidney Disease among Older Veterans

In a breakthrough study focusing on older veterans with chronic kidney disease (CKD), researchers have discovered a potential game-changer in the form of statin initiation. The study, employing a target trial emulation design, aimed to investigate the impact of statin use on all-cause mortality and major adverse cardiovascular events (MACE) in veterans aged over 65 with CKD stages 3 to 4. The study found that Statin initiation in US veterans over 65 with CKD stages 3 to 4 and no prior atherosclerotic cardiovascular disease (ASCVD) was associated with a lower risk of all-cause mortality but did not significantly impact the occurrence of MACE

The study results were published in the journal JAMA Network Open. 

Also Read: Novel hypolipidemic bempedoic acid safe in diabetics, may overcome shortcomings of statins: Lancet

Atherosclerotic cardiovascular disease is the leading cause of death among adults with chronic kidney disease. Some evidence supports the use of statins for the primary prevention of ASCVD in older patients with CKD. While statins are widely known for their efficacy in preventing cardiovascular events, their utility in individuals with CKD has been a subject of limited data and exploration. Due to uncertainty in the evidence researchers from Massachusetts conducted a study to evaluate the association of statin use with all-cause mortality and major adverse cardiovascular events (MACE) among US veterans older than 65 years with CKD stages 3 to 4

The study was conducted as a cohort study, by utilizing a target trial emulation design and involving veterans diagnosed with moderate CKD between 2005 and 2015. Participants were aged over 65, within 5 years of CKD diagnosis, without prior atherosclerotic cardiovascular disease (ASCVD) or statin use, and had at least 1 clinical visit in the year before the trial baseline. Propensity weighting was applied for a meticulous analysis of the outcomes.

Findings:

  • The comprehensive analysis included 14,828 veterans, with a mean age of 76.9 years at CKD diagnosis.
  • The results, after propensity score adjustment, were striking.
  • Statin initiators exhibited a significantly lower risk of all-cause mortality (hazard ratio 0.91, 95% CI 0.85-0.97) compared to noninitiators.
  • This finding suggests a noteworthy association between statin initiation and a reduced risk of mortality in this specific population.
  • However, the study did not find a significant impact on the occurrence of major adverse cardiovascular events (MACE) with statin use.
  • The hazard ratio for MACE was 0.96 (95% CI 0.91-1.02), indicating that statin initiation did not result in a statistically significant reduction in MACE.

These findings carry significant implications for the management of CKD in older veterans. While statin initiation demonstrated a clear association with lower all-cause mortality, the lack of a substantial impact on MACE suggests a need for further research.

Also Read: Statin Use and lowering of Cholesterol may reduce Breast Cancer Mortality

The study underscores the importance of considering statin therapy in the care plan for older veterans with CKD, emphasizing the potential for mortality reduction. However, the researchers emphasize the necessity for confirmation through randomized clinical trials to establish a robust evidence base and inform clinical guidelines.

Further reading: Barayev O, Hawley CE, Wellman H, et al. Statins, Mortality, and Major Adverse Cardiovascular Events Among US Veterans With Chronic Kidney Disease. JAMA Netw Open. 2023;6(12):e2346373. doi:10.1001/jamanetworkopen.2023.46373

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Aspirin use may significantly delay progression of Abdominal Aortic Aneurysm with favorable safety profile.

The preclinical research indicates that aspirin may play a role in slowing the progression of abdominal aortic aneurysms (AAAs) and averting their rupture. However, human studies are scarce to demonstrate the clinical advantages of aspirin in treating AAA.

In a recent retrospective study of a clinical cohort of 3435 patients with objectively measured changes in aortic aneurysm progression, aspirin usage slowed the progression of abdominal aortic aneurysm (AAA) with a favorable safety profile.

This original Investigation on Cardiology was published in JAMA Network Open.

This retrospective study included adult patients with at least two vascular ultrasounds available at the Cleveland Clinic. Patients with a history of aneurysm repair, dissection, or rupture were excluded. All patients were followed for ten years, and clinical outcomes were analyzed from May 2022 to July 2023. The primary outcomes were the time-to-first occurrence of all-cause mortality, major bleeding, or a composite of dissection, rupture, and repair. Multivariable-adjusted Cox proportional-hazard regression and Fine and Gray proportional subhazard regression were used.

Key summary points of this investigation are:

  • There were 2672 male patients with a mean age of 73 years.
  • The median follow-up duration was 4.9 years.
  • Two thousand one hundred fifty patients were verified to be taking aspirin by prescription.
  • Patients taking aspirin had a slower mean annualized change in aneurysm diameter (2.8 vs 3.8 mm per year ) and lower odds of having rapid aneurysm progression compared to patients who were not taking aspirin.
  • The adjusted odds ratio was 0.64.
  • There was no association between aspirin use and risk of all-cause mortality, major bleeding and composite outcome with aHR of 0.92, 0.88 and 1.16, respectively.

They said that in this study, aspirin use slowed the progression of abdominal aortic aneurysms, especially in men and nonsmokers. Aspirin use was not associated with all-cause mortality, major bleeding, or the risk of aneurysm dissection, rupture, or repair after ten years.

Reference:

Hariri E, Matta M, Layoun H, et al. Antiplatelet Therapy, Abdominal Aortic Aneurysm Progression, and Clinical Outcomes. JAMA Netw Open. 2023;6(12):e2347296

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High resting heart rate may be risk factor for end-stage renal disease

High resting heart rate may independent risk factor for end-stage renal disease suggests a new study published in the Journal of the American Heart Association. 

The relationship between resting heart rate (RHR) and the risk of end‐stage renal disease (ESRD) among those without cardiovascular disease remains unclear. We aim to establish temporal consistency and elucidate the independent relationship between RHR and the risk of ESRD.

This cohort enrolled participants from 476 347 individuals who had taken part in a screening program from 1996 to 2017. We identified 2504 participants who had ESRD, and the median follow‐up was 13 years. RHR was extracted from electrocardiography results, and the study assessed the relationship between RHR and the risk of ESRD using the Cox proportional hazards model. Of the participants, 32.6% had an RHR of 60 to 69 beats per minute (bpm), and 22.2% had an RHR of ≥80 bpm. Participants with an RHR of ≥80 bpm had a higher stage of chronic kidney disease, lower estimated glomerular filtration rate, and more proteinuria than those with an RHR of 60 to 69 bpm. Participants with an RHR of 80 to 89 and ≥90 bpm had a 24% (hazard ratio [HR], 1.24 [95% CI, 1.09–1.42]) and 64% (HR, 1.64 [95% CI, 1.42–1.90]) higher risk of ESRD, respectively. The risk of ESRD remained significantly elevated (HR, 1.32 [95% CI, 1.10–1.58] per 10‐beat increase from 60 bpm) after excluding participants who smoked; had hypertension, diabetes, or hyperlipidemia; or were overweight.

An RHR of ≥80 bpm is significantly associated with an increased risk of ESRD. These results suggest that RHR may serve as a risk factor for kidney disease in individuals without established cardiovascular disease risk factors.

Reference:

Resting Heart Rate Independent of Cardiovascular Disease Risk Factors Is Associated With End‐Stage Renal Disease: A Cohort Study Based on 476 347 Adults

Min‐Kuang Tsai, Wayne Gao, Kuo‐Liong Chien, Thu Win Kyaw, Chin‐Kun Baw, Chih‐Cheng Hsu and Chi‐Pang Wen. Originally published1 Dec 2023https://doi.org/10.1161/JAHA.123.030559Journal of the American Heart Association. 2023;12:e030559

Keywords:

High, resting, heart, rate, may, independent, risk, factor, for, end-stage, renal, disease, Journal of the American Heart Association, Min‐Kuang Tsai, Wayne Gao, Kuo‐Liong Chien, Thu Win Kyaw, Chin‐Kun Baw, Chih‐Cheng Hsu and Chi‐Pang We

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Elagolix monotherapy Safe Against Heavy Menstrual Bleeding associated with Uterine Leiomyomas

A new phase 4 study published in The Journal of Obstetrics and Gynecology found elagolix 150 mg monotherapy taken once-daily to solve heavy menstrual bleeding associated with uterine leiomyomas were the safe and effective. This offers promise to premenopausal patients aged 18–51 years.

This randomized, double-blind, placebo-controlled study assessed  a total of 82 patients, with 54 receiving elagolix 150 mg and 28 receiving a placebo. The primary endpoint was a reduction in menstrual blood loss volume to less than 80 mL at the final month, coupled with at least a 50% reduction from baseline to the final month.

The results found 49.4% of patients in the elagolix group who met the primary endpoint, compared with 23.3% in the placebo group (P=.035). The differences in mean reduction of menstrual blood loss were significant as early as month 1 (P<.05 for months 1–3 and 5).

Moreover, elagolix demonstrated its effectiveness in suppressing bleeding (P=.036). The patients on elagolix experienced greater improvements in the proportion of those with amenorrhea, hemoglobin concentrations, and health-related quality of life.

Elagolix treatment was well-tolerated. There were no serious or severe adverse events reported, in stark contrast to the 7.1% of participants in the placebo group facing serious adverse events, including coronavirus disease 2019 (COVID-19) and an enlarged uvula. Only 5.6% of patients discontinued elagolix due to adverse events.

This study brings out a significant improvement in addressing heavy menstrual bleeding associated with uterine leiomyomas in premenopausal patients. The positive outcomes of elagolix 150 mg once-daily monotherapy, coupled with its favorable safety profile, underscore its potential as a transformative treatment option.

Source:

Brown, E., Kroll, R., Li, H., Ng, J., Pinsky, B., Rodriguez, J. W., Thomas, J., & Snabes, M. C. (2023). Low-dose elagolix for the treatment of heavy menstrual bleeding in patients with uterine leiomyomas: A randomized controlled trial. Obstetrics and Gynecology, 142(5), 1068–1076. https://doi.org/10.1097/aog.0000000000005380

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