New Horizons of Model Informed Drug Development in Rare Diseases Drug Development.

Model-informed approaches provide a quantitative framework to integrate all available nonclinical and clinical data, thus furnishing a totality of evidence approach to drug development and regulatory evaluation. Maximizing the use of all available data and information about the drug enables a more robust characterization of the risk-benefit profile and reduces uncertainty in both technical and regulatory success. This offers the potential to transform rare diseases drug development, where conducting large well-controlled clinical trials is impractical and/or unethical due to a small patient population, a significant portion of which could be children. Additionally, the totality of evidence generated by model-informed approaches can provide confirmatory evidence for regulatory approval without the need for additional clinical data. In the article, applications of novel quantitative approaches such as quantitative systems pharmacology, disease progression modeling, artificial intelligence, machine learning, modeling of real-world data using model-based meta-analysis and strategies such as external control and patient-reported outcomes as well as clinical trial simulations to optimize trials and sample collection are discussed. Specific case studies of these modeling approaches in rare diseases are provided to showcase applications in drug development and regulatory review. Finally, perspectives are shared on the future state of these modeling approaches in rare diseases drug development along with challenges and opportunities for incorporating such tools in the rational development of drug products.

Environmental impact of phytobiotic additives on greenhouse gas emission reduction, rumen fermentation manipulation, and performance in ruminants: an updated review.

Ruminal fermentation is a natural process involving beneficial microorganisms that contribute to the production of valuable products and efficient nutrient conversion. However, it also leads to the emission of greenhouse gases, which have detrimental effects on the environment and animal productivity. Phytobiotic additives have emerged as a potential solution to these challenges, offering benefits in terms of rumen fermentation modulation, pollution reduction, and improved animal health and performance. This updated review aims to provide a comprehensive understanding of the specific benefits of phytobiotic additives in ruminant nutrition by summarizing existing studies. Phytobiotic additives, rich in secondary metabolites such as tannins, saponins, alkaloids, and essential oils, have demonstrated biological properties that positively influence rumen fermentation and enhance animal health and productivity. These additives contribute to environmental protection by effectively reducing nitrogen excretion and methane emissions from ruminants. Furthermore, they inhibit microbial respiration and nitrification in soil, thereby minimizing nitrous oxide emissions. In addition to their environmental impact, phytobiotic additives improve rumen manipulation, leading to increased ruminant productivity and improved quality of animal products. Their multifaceted properties, including anthelmintic, antioxidant, antimicrobial, and immunomodulatory effects, further contribute to the health and well-being of both animals and humans. The potential synergistic effects of combining phytobiotic additives with probiotics are also explored, highlighting the need for further research in this area. In conclusion, phytobiotic additives show great promise as sustainable and effective solutions for improving ruminant nutrition and addressing environmental challenges.

Advancing the utilization of real-world data and real-world evidence in clinical pharmacology and translational research-Proceedings from the ASCPT 2023 preconference workshop.

Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research." The work described herein is a summary of the workshop proceedings.

The renoprotective activity of amikacin-gamma-amino butyric acid-chitosan nanoparticles: a comparative study.

The development of nanoparticles (NPs) with active components with upgraded stability, and prolonged release helps in enhanced tissue regeneration. In addition, NPs are feasible strategy to boost antibiotic effectiveness and reduce drug side effects. Our study focuses on the use of amikacin (AMK) and gamma amino butyric acid (GABA) unloaded combinations or loaded on chitosan nanoparticles (CSNPs) for kidney protection. The AMK-GABA-CSNPs were prepared with the ionic gelation method, the morphology was studied using transmission electron microscopy (TEM), zetasizer and the Fourier transform-infrared spectroscopy (FT-IR) spectrum of the synthesized NPs was observed. The average size of AMK-GABA-CSNPs was 77.5 ± 16.5 nm. Zeta potential was + 38.94 ± 2.65 mV. AMK-GABA-CSNPs revealed significant in vitro antioxidant, anti-coagulation, non-hemolytic properties and good cell compatibility. To compare the effects of the unloaded AMK-GABA combination and AMK-GABA-CSNPs on the renal tissue, 42 healthy Sprague-Dawley rats were divided into seven groups. G1: normal control (NC), normal saline; G2: low-dose nephrotoxic group (LDN), AMK (20 mg/kg/day; i.p.); G3: unloaded AMK (20 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.); G4: AMK-GABA-CSNPs (20 mg/kg/day; i.p.); G5: high-dose nephrotoxic group (HDN), AMK (30 mg/kg/day; i.p.); G6: unloaded AMK (30 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.) and G7: AMK-GABA-CSNPs (30 mg/kg/day; i.p.). The results showed that AMK-GABA-CSNPs formulation is superior to unloaded AMK-GABA combination as it ameliorated kidney functions, oxidative stress and displayed a significant homeostatic role via suppression of inflammatory cytokines of Th1, Th2 and Th17 types. Hence, AMK-GABA-CSNPs could afford a potential nano-based therapeutic formula for the management of AMK-nephrotoxicity.

Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.

Lanadelumab in Patients 2 to Less Than 12 Years Old With Hereditary Angioedema: Results From the Phase 3 SPRING Study.

BACKGROUND: Symptoms of hereditary angioedema (HAE) often first occur during childhood, and HAE attacks in children can be severe and substantially affect health-related quality of life (HRQoL). However, there are no approved long-term prophylaxis treatments for children aged less than 6 years. OBJECTIVE: The SPRING Study (NCT04070326) evaluated the safety, pharmacokinetics, and efficacy of lanadelumab and HRQoL in patients aged 2 to less than 12 years. METHODS: Over 52 weeks of treatment, patients aged 2 to less than 6 years received lanadelumab 150 mg every 4 weeks (Q4W) and patients aged 6 to less than 12 years received 150 mg every 2 weeks (Q2W) but could switch to Q4W if they were attack-free for 26 weeks. RESULTS: We enrolled 21 patients (aged 2 to less than 6 years: n = 4; aged 6 to less than 12 years: n = 17), 20 of whom completed the study. There were no reported serious treatment-emergent adverse events or discontinuations resulting from such events. Treatment-emergent adverse events were reported for 17 patients (81.0%). The most common TEAE was injection site pain. Overall systemic exposure was comparable for both age groups. The mean (SD) attack rate during treatment decreased by 94.8% from baseline (1.84 [1.53] to 0.08 [0.17] attacks/mo), and 16 (76.2%) patients were attack-free. The attack rate reduction in both age groups was similar during the first 26-week fixed-dosing treatment. Seven patients switched from Q2W to Q4W and remained attack-free. A large, clinically meaningful increase in the Pediatric Quality of Life Inventory Generic Core Scale Total Score and a large increase in the Pediatric Quality of Life Inventory Generic Core Scale-Family Impact Module Total Score from baseline to end of study (better HRQoL) were observed. CONCLUSIONS: Findings support safety, efficacy, and improved HRQoL with lanadelumab 150 mg Q2W and Q4W regimens for the prevention of HAE attacks in patients aged 2 to less than 12 years.

Eobania vermiculata whole-body muscle extract-loaded chitosan nanoparticles enhanced skin regeneration and decreased pro-inflammatory cytokines in vivo.

BACKGROUND: Usually, wounds recover in four to six weeks. Wounds that take longer time than this to heal are referred to as chronic wounds. Impaired healing can be caused by several circumstances like hypoxia, microbial colonization, deficiency of blood flow, reperfusion damage, abnormal cellular reaction and deficiencies in collagen production. Treatment of wounds can be enhanced through systemic injection of the antibacterial drugs and/or other topical applications of medications. However, there are a number of disadvantages to these techniques, including the limited or insufficient medication penetration into the underlying skin tissue and the development of bacterial resistance with repeated antibiotic treatment. One of the more recent treatment options may involve using nanotherapeutics in combination with naturally occurring biological components, such as snail extracts (SE). In this investigation, chitosan nanoparticles (CS NPs) were loaded with an Eobania vermiculata whole-body muscle extract. The safety of the synthesized NPs was investigated in vitro to determine if these NPs might be utilized to treat full-skin induced wounds in vivo. RESULTS: SEM and TEM images showed uniformly distributed, spherical, smooth prepared CS NPs and snail extract-loaded chitosan nanoparticles (SE-CS NPs) with size ranges of 76-81 and 91-95 nm, respectively. The zeta potential of the synthesized SE-CS NPs was - 24.5 mV, while that of the CS NPs was 25 mV. SE-CS NPs showed a remarkable, in vitro, antioxidant, anti-inflammatory and antimicrobial activities. Successfully, SE-CS NPs (50 mg/kg) reduced the oxidative stress marker (malondialdehyde), reduced inflammation, increased the levels of the antioxidant enzymes (superoxide dismutase and glutathione), and assisted the healing of induced wounds. SE-CS NPs (50 mg/kg) can be recommended to treat induced wounds safely. SE was composed of a collection of several wound healing bioactive components [fatty acids, amino acids, minerals and vitamins) that were loaded on CS NPs. CONCLUSIONS: The nanostructure enabled bioactive SE components to pass through cell membranes and exhibit their antioxidant and anti-inflammatory actions, accelerating the healing process of wounds. Finally, it is advised to treat rats' wounds with SE-CS NPs.

Model-Informed Approaches and Innovative Clinical Trial Design for Adeno-Associated Viral Vector-Based Gene Therapy Product Development: A White Paper.

The promise of viral vector-based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life-threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno-associated virus (AAV) vector-based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype-phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit-risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model-informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV-based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products.

Ensiling Characteristics, In Vitro Rumen Fermentation Patterns, Feed Degradability, and Methane and Ammonia Production of Berseem (Trifolium alexandrinum L.) Co-Ensiled with Artichoke Bracts (Cynara cardunculus L.).

This study investigated the effect of co-ensiling increasing levels of artichoke bracts (Cynara cardunculus L.) with berseem (Trifolium alexandrinum L.) (100:0, 75:25, 50:50, 25:75, and 0:100, respectively) on silage quality after 0, 30, 60, and 120 days. Moreover, the in vitro rumen fermentation characteristics and methane (CH4) and ammonia (NH3-N) production were evaluated using a buffalo inoculum source. The results showed that pH of the silage and the concentration of acetic, propionic, butyric acid, and NH3-N significantly decreased (L; p < 0.01) with the increasing amounts of artichoke bracts in the mixture. At 30 and 60 days of ensiling, the highest lactic acid concentration was observed at intermediate proportions of artichoke bracts (p < 0.01). Cumulative gas production was higher in artichoke bracts than in the berseem silage. After 24 h of incubation, the highest value (p < 0.05) of truly dry matter, organic matter, natural detergent fiber degradability, and NH3-N concentration was recorded with 500 g/kg of forage mixtures. As the artichoke bract concentration increased, the partitioning factor and ruminal pH declined linearly (p ≤ 0.05). No significant differences were observed for total volatile fatty acids and volatile fatty acids molar proportions. In summary, co-ensiling artichoke bracts with berseem at a ratio of 1:1 might be a promising and easy method for the production of high-quality silage from legume forage with positively manipulating rumen fermentation.

Achieving big with small: quantitative clinical pharmacology tools for drug development in pediatric rare diseases.

Pediatric populations represent a major fraction of rare diseases and compound the intrinsic challenges of pediatric drug development and drug development for rare diseases. The intertwined complexities of pediatric and rare disease populations impose unique challenges to clinical pharmacologists and require integration of novel clinical pharmacology and quantitative tools to overcome multiple hurdles during the discovery and development of new therapies. Drug development strategies for pediatric rare diseases continue to evolve to meet the inherent challenges and produce new medicines. Advances in quantitative clinical pharmacology research have been a key component in advancing pediatric rare disease research to accelerate drug development and inform regulatory decisions. This article will discuss the evolution of the regulatory landscape in pediatric rare diseases, the challenges encountered during the design of rare disease drug development programs and will highlight the use of innovative tools and potential solutions for future development programs.

Heavy migration of flood affectees in Pakistan and increased risk of autism spectrum disorder in children: a call to action.

Autism spectrum disorder (ASD) refers to various neurodevelopmental disabilities generally seen in kids. Pakistan, being vulnerable to natural disasters, faced one of the most devastating floods in July 2022 due to which many individuals were displaced. This not only affected the mental health of growing children but also the developing fetus of migrant mothers. This report establishes the link between the aftereffects of migration due to floods on children particularly associated with ASD in Pakistan. Flood affected families are devoid of basic necessities and are under a lot of psychological stress. On the other hand, Extensive treatment for autism is complicated, expensive, and provided in proper settings only which is not easily accessible to migrants. Considering all these factors, there are chances that ASD will be more prevalent in future generations of these migrants. Our study calls on respective authorities to take timely action for this growing concern.

The effect of urethane and MS-222 anesthesia on the electric organ discharge of the weakly electric fish Apteronotus leptorhynchus.

Urethane and MS-222 are agents widely employed for general anesthesia, yet, besides inducing a state of unconsciousness, little is known about their neurophysiological effects. To investigate these effects, we developed an in vivo assay using the electric organ discharge (EOD) of the weakly electric fish Apteronotus leptorhynchus as a proxy for the neural output of the pacemaker nucleus. The oscillatory neural activity of this brainstem nucleus drives the fish's EOD in a one-to-one fashion. Anesthesia induced by urethane or MS-222 resulted in pronounced decreases of the EOD frequency, which lasted for up to 3 h. In addition, each of the two agents caused a manifold increase in the generation of transient modulations of the EOD known as chirps. The reduction in EOD frequency can be explained by the modulatory effect of urethane on neurotransmission, and by the blocking of voltage-gated sodium channels by MS-222, both within the circuitry controlling the neural oscillations of the pacemaker nucleus. The present study demonstrates a marked effect of urethane and MS-222 on neural activity within the central nervous system and on the associated animal's behavior. This calls for caution when conducting neurophysiological experiments under general anesthesia and interpreting their results.

Xanthotoxin modulates oxidative stress, inflammation, and MAPK signaling in a rotenone-induced Parkinson's disease model.

AIMS: Parkinson's disease (PD) is characterized by motor disabilities precipitated by α-synuclein aggregation and dopaminergic neurodegeneration. The roles of oxidative stress, neuroinflammation, dysfunction of the mitogen-activated protein kinase (MAPK) pathway, and apoptosis in dopaminergic neurodegeneration have been established. We investigated the potential neuroprotective effect of xanthotoxin, a furanocoumarin extracted from family Apiaceae, in a rotenone-induced PD model in rats since it has not yet been elucidated. MAIN METHODS: For 21 days, rats received 11 rotenone injections (1.5 mg/kg, s.c.) on the corresponding days to induce a PD model and xanthotoxin (15 mg/kg, i.p.) daily. KEY FINDINGS: Xanthotoxin preserved dopaminergic neurons and restored tyrosine hydroxylase positive cells, with suppression of α-synuclein accumulation and restoration of striatal levels of dopamine and its metabolites resulting in amelioration of motor deficits. Furthermore, xanthotoxin impeded rotenone-stimulated neurodegeneration by reducing oxidative stress, which was confirmed by malondialdehyde suppression and glutathione antioxidant enzyme augmentation. It also suppressed neurotoxic inflammatory mediators including tumor necrosis factor-α, interleukin-1ß, and inducible nitric oxide synthase. Additionally, xanthotoxin attenuated the rotenone-mediated activation of MAPK kinases, C-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinases 1/2, with consequent ablation of apoptotic mediators including Bax, cytochrome c, and caspase-3. SIGNIFICANCE: This study revealed the neuroprotective effect of xanthotoxin in a rotenone-induced PD model in rats, an action that could be attributed to its antioxidant, anti-inflammatory activities as well as to its ability to maintain the function of the MAPK signaling pathway and attenuate apoptosis. Therefore, it could be a valuable therapy for PD.

Alcohol impairs recognition and uptake of Mycobacterium tuberculosis by suppressing toll-like receptor 2 expression.

BACKGROUND: Alcohol impairs pulmonary innate immune function and is associated with an increased risk of tuberculosis (TB). Toll-like receptor 2 (TLR2) is a pattern recognition receptor on alveolar macrophages that recognizes Mycobacterium tuberculosis (Mtb). The expression of TLR2 depends, in part, on granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Given our prior work demonstrating the suppression of GM-CSF signaling following chronic alcohol ingestion, we hypothesized that alcohol impairs TLR2 expression via the suppression of GM-CSF and thereby reduces the ability of the macrophage to recognize and phagocytose Mtb. METHODS: Primary alveolar macrophages were isolated from control-fed and alcohol-fed rats. Prior to cell isolation, some alcohol-fed rats were treated with intranasal GM-CSF and then endotracheally inoculated with an attenuated strain of Mtb. Primary macrophages were then isolated and immunofluorescence was used to determine phagocytic efficiency and TLR2 expression in the presence and absence of GM-CSF treatment and phagocytic efficiency in the presence and absence of TLR2 neutralization. RESULTS: TLR2 expression and phagocytosis of Mtb were significantly lower in the alveolar macrophages of alcohol-fed rats than control-fed rats. In parallel, blocking TLR2 signaling recapitulated this decreased phagocytosis of Mtb. In contrast, intranasal GM-CSF treatment restored TLR2 expression and Mtb phagocytosis in the alveolar macrophages of alcohol-fed rats to levels comparable to those of control-fed rats. CONCLUSIONS: Chronic alcohol ingestion reduces TLR2 protein expression and phagocytosis of Mtb, likely due to impaired GM-CSF signaling. GM-CSF restores membrane-bound TLR2 expression and phagocytic function.

Potential of selected plant extracts to control severe subacute ruminal acidosis in vitro as compared with monensin.

BACKGROUND: In recent years, researchers have become increasingly interested in developing natural feed additives that can stabilize ruminal pH and thus prevent or eliminate the risk of severe subacute rumen acidosis. Herein, 3 experiments were conducted using a semi-automated in vitro gas production technique. In the experiment (Exp.) 1, the efficacy of 9 plant extracts (1.5 mg/ml), compared to monensin (MON; 12 µg/ml), to counteract ruminal acidosis stimulated by adding glucose (0.1 g/ml) as a fermentable carbohydrate without buffer was assessed for 6 h. In Exp. 2, cinnamon extract (CIN) and MON were evaluated to combat glucose-induced acidosis with buffer use for 24 h. In Exp. 3, the effect of CIN and MON on preventing acidosis when corn or barley grains were used as substrate was examined. RESULTS: In Exp. 1, cinnamon, grape seeds, orange, pomegranate peels, propolis, and guava extracts significantly increased (P < 0.05) pH compared to control (CON). Both CIN and MON significantly increased the pH (P < 0.001) but reduced cumulated gas production (P < 0.01) compared to the other treatments. In Exp. 2, the addition of CIN extract increased (P < 0.01) pH value compared to CON at the first 6 h of incubation. However, no significant differences in pH values between CIN and CON at 24 h of incubation were observed. The addition of CIN extract and MON decreased (P < 0.001) lactic acid concentration and TVFA compared to CON at 24 h. The CIN significantly (P < 0.01) increased acetate: propionate ratio while MON reduced it. In Exp. 3, both CIN and MON significantly increased (P < 0.05) ruminal pH at 6 and 24 h and reduced lactic acid concentration at 24 h compared to CON with corn as substrate. However, CIN had no effect on pH with barley substrate at all incubation times. CONCLUSIONS: It can be concluded that CIN can be used effectively as an alternative antibiotic to MON to control ruminal acidosis when corn is used as a basal diet.

Biological Extraction, HPLC Quantification and Medical Applications of Astaxanthin Extracted from Crawfish "Procambarus clarkii" Exoskeleton By-Product.

The main challenge of astaxanthin extraction is to provide an eco-friendly method of extraction instead of chemical methods that harm human health. This study provided an eco-friendly method for astaxanthin extraction using two bacterial and fungal probiotics (Bifidobacterium lactis, Lactobacillus lactis, Candida utilis, and Saccharomyces cerevisiae, respectively) and determined the astaxanthin concentration by high-performance liquid chromatography (HPLC) analysis. The results showed that the highest concentration was obtained by S. cerevisiae (45.69 µg/g). Several biological tests were done on the exoskeleton containing astaxanthin of crawfish. Antifungal activity was effective against C. utilis (inhibition zone is 12.3 ± 0.5 mm). The scavenging percentage of 2,2-diphenyl-1-picrylhydrazyl (DPPH scavenging percentage) was 72.1% at 1000 µg/mL concentration of exoskeleton containing astaxanthin. The Hemolysis inhibition percentage was 65% at the same concentration used previously. Furthermore, the IC50 value of human liver cancer cell line (HepG2), human hepatocellular carcinoma (HCT), and breast cancer cell line MCF-7 were 24 µg/mL, 11 µg/mL, and 9.5 µg/mL, respectively. The least cell viability percentage was 19% (using breast cancer cell line (MCF-7)) at 100 µg/mL of exoskeleton containing astaxanthin. Thus, using microorganisms can be an alternative and promising way of astaxanthin extraction. Furthermore, purification of extracted astaxanthin is essential for medical applications.

Clinical Pharmacology in Drug Development for Rare Diseases in Neurology: Contributions and Opportunities.

Several challenges are associated with rare disease drug development in neurology. In this article, we summarize the US Food and Drug Administration's experience with clinical drug development for rare neurological diseases and discuss clinical pharmacology's critical contributions to drug development for rare diseases. We used publicly available information to identify and screen drug products approved for rare neurological indications between 1983 and 2019. We highlighted cases in which clinical pharmacology contributed to the evidence of drug efficacy, dose selection for pivotal clinical trials, dose optimization based on intrinsic and extrinsic factors, pharmacokinetic bridging for formulations, and efficacy bridging across different racial groups. Fifty-one approved drug products were identified since the introduction of the Orphan Drug Act in 1983. Interestingly, the number of approvals in the last few years increased significantly, probably due to advances in genomic research and targeted drug modalities. Evaluation of dose selection in patient populations showed that in 52% of cases, the sponsors did not evaluate efficacy for more than one or two dose levels throughout the development program. Clinical pharmacology studies to evaluate the effect of intrinsic or extrinsic factors were adequately characterized in most of the applications. With the expansion of model informed drug development applications, (e.g., quantitative systems pharmacology and deep learning neural network models), the role and impact of clinical pharmacology is expected to grow exponentially in the next decade and enhance the development of novel treatment modalities for neurological rare diseases.

Efficacy of Hibiscus sabdariffa on Reducing Blood Pressure in Patients With Mild-to-Moderate Hypertension: A Systematic Review and Meta-Analysis of Published Randomized Controlled Trials.

We aimed to assess the efficacy of Hibiscus sabdariffa in patients with mild-to-moderate hypertension or metabolic syndrome (MetS) by comparing it against placebo, antihypertensive drugs, or other herbal products. Four databases were searched for randomized clinical trials (RCTs) examining the efficacy of H. sabdariffa in patients with mild-to-moderate hypertension or hypertension associated with MetS. Data on the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were extracted and analyzed using Review Manager Version 5.3. A total of 13 RCTs (1205 participants) were analyzed. Hibiscus sabdariffa significantly reduced both SBP and DBP compared with placebo (mean difference -6.67, P = 0.004 and -4.35 mm Hg, P = 0.02). Subgroup analysis showed that change in SBP and DBP was statistically significant in patients with only hypertension, whereas not significant in patients with hypertension associated with MetS. When H. sabdariffa was compared with active controls (antihypertensive drugs or other herbals), the change in SBP and DBP was not statistically significant (all P > 0.05). Hibiscus sabdariffa is effective in reducing the SBP and DBP in patients with mild-to-moderate hypertension, but was neither effective in those with MetS nor superior to antihypertensive drugs. Further RCTs are required to determine the long-term efficacy of H. sabdariffa and to describe patients who would benefit most from this treatment.