METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.
RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan.
CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
AIM OF THE STUDY: To explore the antinociceptive (acute pain) and anti-neuropathic (chronic pain) activities of Lotus corniculatus leaves essential oil (LCEO) in addition to uncovering the possible mechanisms of antinociception.
MATERIALS AND METHODS: LCEO as well as the pure oleanolic acid (OA) compound, were assayed for their effects on acute (formalin induced paw licking test or FIPT) and chronic (cervical contusion injury models on the fifth cervical vertebra or CCS; 14-day intervals) pain. The possible involvements of NO-cGMP-K+ channel, TRPV, dopamine, cannabinoid, PPAR, adrenergic, and opioid mechanisms in the antinociceptive activity of LCEO have studied by formalin test. The levels of p53 and inflammatory markers were measured using a streptavidin biotin immune peroxidase complex and ELISA methods, respectively.
RESULTS: The LCEO and OA exerted antinociceptive activity in the first-phase of FIPT. Pretreatment with antagonists of TRPV1, dopamine D2, cannabinoid type1 and 2, and NO-cGMP-K+ channel blockers (glibenclamide, L-NAME and methylene blue) attenuated the antinociceptive effect of LCEO in FIPT. In addition, LCEO and OA meaningfully reduced hyperalgesia (days 6-14) and mechanical allodynia (days 2-14) in the CCS model. LCEO suppressed the apoptotic marker (p53) in CCS model and also ameliorated IL-2, TNF-α, and IL-1 in the spinal cord.
CONCLUSION: Finally, LCEO inhibited acute (possibly via the modulation of opioid, TRPV, dopamine, cannabinoid mechanisms as well as NO-cGMP-K+ channel) and chronic pain (via suppressing apoptotic and inflammatory markers) in male rats. The results also suggest that OA has analgesic activity against acute and chronic pain conditions.
OBJECTIVE: This research was proposed to develop a co-processed excipient composed of xylitol, mannitol, and microcrystalline cellulose for the formulation of ODTs.
METHODS: A total of 11 formulations of co-processed excipients with different ratios of ingredients were prepared, which were then compressed into ODTs, and their characteristics were thoroughly examined. The primary focus was on evaluating the disintegration time and hardness of the tablets, as these factors are important in ensuring the ODTs meet the desired criteria. The model drug, Mirtazapine was then incorporated into the chosen optimized formulation.
RESULTS: The results showed that the formulation comprised of 10% xylitol, 10% mannitol and 80% microcrystalline cellulose demonstrated the fastest disintegration time (1.77 ± 0.119 min) and sufficient hardness (3.521 ± 0.143 kg) compared to the other formulations. Furthermore, the drug was uniformly distributed within the tablets and fully released within 15 min.
CONCLUSION: Therefore, the developed co-processed excipients show great potential in enhancing the functionalities of ODTs, offering a promising solution to improve the overall performance and usability of ODTs in various therapeutic applications.
MATERIALS AND METHODS: Seventy-five participants underwent MRE as an initial investigation or follow-up for inflammatory bowel disease. A systematic sampling method was used to divide the participants into three different groups: group 1 received 6.7% mannitol concentration, group 2 received 3.3% mannitol concentration and group 3 received pineapple juice as an oral contrast agent during their MRE examination. The degree of bowel distension on MRE images was assessed by a radiologist by measuring the bowel diameter from inner wall to inner wall at specified levels, while qualitative analysis was evaluated based on the presence of artefacts. All patients were asked to score their acceptance of the oral contrast and were asked about side effects such as diarrhoea, abdominal discomfort and vomiting.
RESULTS: All patients were able to completely ingest 1.5L of oral contrast. The mean diameter of bowel distension was 2.1cm in patients who received 6.7% mannitol concentration, 2.0cm in patients who received 3.3% mannitol concentration and 1.6 cm in patients who received pineapple juice. Twothirds of patients who received 6.7% mannitol and 3.3% mannitol solutions had good-quality MRE images, but 68% of patients who received pineapple juice had poor-quality MRE images. Twenty-four patients (96%) who received pineapple juice rated it as slightly acceptable and acceptable but only 12 patients (48%) who received 6.7% mannitol solution rated it as slightly acceptable and acceptable. Eighty-eight percent of patients who received 6.7% mannitol solution experienced at least one form of side effect as compared to 44% of patients who received 3.3% mannitol solution and 18% of patients who received pineapple juice.
CONCLUSION: Optimum small bowel distension and good image quality can be achieved using 3.3% mannitol concentration as an oral contrast agent. Increase in mannitol concentration does not result in significant improvement of small bowel distension or image quality but is instead related to poorer patient acceptance and increased side effects. Pineapple juice is more palatable than mannitol and produces satisfactory small bowel distension. However, the small bowel distension is less uniform when using pineapple juice with a considerable presence of artefacts. Mannitol, 3.3% concentration, is therefore recommended as an endoluminal contrast agent for bowel in MRE.
AIMS OF THE STUDY: This study aims to investigate the ability of T. diffusa to ameliorate the impairment in testicular steroidogenesis and spermatogenesis in DM that might help to improve testicular function, and subsequently restore male fertility.
MATERIALS AND METHODS: DM-induced adult male rats were given 100 mg/kg/day and 200 mg/kg/day T. diffusa leaf extract orally for 28 consecutive days. Rats were then sacrificed; sperm and testes were harvested and sperm parameter analysis were performed. Histo-morphological changes in the testes were observed. Biochemical assays were performed to measure testosterone and testicular oxidative stress levels. Immunohistochemistry and double immunofluorescence were used to monitor oxidative stress and inflammation levels in testes as well as Sertoli and steroidogenic marker proteins' expression.
RESULTS: Treatment with T. diffusa restores sperm count, motility, and viability near normal and reduces sperm morphological abnormalities and sperm DNA fragmentation in diabetic rats. T. diffusa treatment also reduces testicular NOX-2 and lipid peroxidation levels, increases testicular antioxidant enzymes (SOD, CAT, and GPx) activities, ameliorates testicular inflammation via downregulating NF-ΚB, p-Ikkβ and TNF-α and upregulating IκBα expression. In diabetic rats, T. diffusa treatment increases testicular steroidogenic proteins (StAR, CYP11A1, SHBG, and ARA54, 3 and 17β-HSD) and plasma testosterone levels. Furthermore, in diabetic rats treated with T. diffusa, Sertoli cell marker proteins including Connexin 43, N-cadherin, and occludin levels in the testes were elevated.
CONCLUSION: T. diffusa treatment could help to ameliorate the detrimental effects of DM on the testes, thus this plant has potential to be used to restore male fertility.
METHODS: The liquids were adsorbed on microcrystalline cellulose, and all developed formulations were compressed using 10.5 mm shallow concave round punches.
RESULTS: The resulting tablets were evaluated for different quality-control parameters at pre- and postcompression levels. Simvastatin showed better solubility in a mixture of oils and Tween 60 (10:1). All the developed formulations showed lower self-emulsification time (˂200 seconds) and higher cloud point (˃60°C). They were free of physical defects and had drug content within the acceptable range (98.5%-101%). The crushing strength of all formulations was in the range of 58-96 N, and the results of the friability test were within the range of USP (≤1). Disintegration time was within the official limits (NMT 15 min), and complete drug release was achieved within 30 min.
CONCLUSION: Using commonly available excipients and machinery, SEDDS-based tablets with better dissolution profile and bioavailability can be prepared by direct compression. These S-SEDDSs could be a better alternative to conventional tablets of simvastatin.
METHODS: The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and% transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS.
RESULTS: The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension).
CONCLUSION: The LPV-SNEDDS could be a potential carrier for LPV oral delivery.
OBJECTIVE: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline.
DESIGN, SETTING, AND PARTICIPANTS: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021.
INTERVENTIONS: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group).
MAIN OUTCOMES AND MEASURES: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure.
RESULTS: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01560052.
METHODS: This study utilised in-patient data from the case mix unit of Universiti Kebangsaan Malaysia Medical Centre (UKMMC) between 2011 and 2018. Direct medical costs of stroke were determined using a top-down costing approach and factors associated with costs were identified. Incremental cost effectiveness ratio (ICER) was calculated to compare the cost-effectiveness between DOACs and warfarin.
RESULTS: The direct medical cost of stroke was MYR 11,669,414.83 (n = 3689). AF-related stroke cases had higher median cost of MYR 2839.73 (IQR 2269.79-3101.52). Regression analysis showed that stroke type (AF versus non-AF stroke) (p = 0.013), stroke severity (p = 0.010) and discharge status (p < 0.001) significantly influenced stroke costs. DOACs were cost-effective compared to warfarin with an ICER of MYR 19.25.
CONCLUSIONS: The direct medical cost of stroke is substantial, with AF-stroke having a higher median cost per stroke care. DOACs were cost effective in the treatment of AF-related stroke in UKMMC.
METHODS: Drug formulations were administered to the experimental animals via oral, intravenous and intraperitoneal routes. Blood samples were collected at different pre-determined time intervals to determine the pharmacokinetic parameters. To understand the biodistribution profile of HCZ, tissue samples were isolated from different groups of Sprague-Dawley rats at different time points. The pharmacokinetic parameters of HZC were evaluated after administration through oral (100 mg/kg), intraperitoneal (100 mg/kg) and intravenous (10 mg/kg) routes.
RESULTS: Significantly (p oral administration at a similar dose. In addition, shorter time to peak was observed with intraperitoneal administration. These results revealed a faster rate and longer duration of absorption with intraperitoneal administration, which further resulted in enhanced absolute bioavailability of HZC (29.17%) when compared to 5.1% upon oral dosing. The obtained data from the pharmacokinetic study indicated that HZC was instantaneously distributed and moderately eliminated from body fluids.
CONCLUSION: Based on the findings, it could be concluded that absorption of HZC is much higher via intraperitoneal route of administration compared to the oral administration.
PATIENTS AND METHODS: This was a multinational, multicentre, non-interventional study involving 49 sites across 5 countries in South East Asia and South Korea where 934 patients newly diagnosed with NVAF were initiated on either dabigatran (N=591) or VKA (N=343). Data were collected at baseline and over two follow-up visits across 6 months. Treatment satisfaction and patient convenience were evaluated using the Perception on Anticoagulant Treatment Questionnaire-2 (PACT-Q2).
RESULTS: The mean age of the patients was 65.9±10.4 years, and 64.2% were male. Mean CHA2DS2-VASc score was 2.4±1.5, and mean HAS-BLED score was 1.2±0.9. At baseline, patients initiated on dabigatran had higher stroke risk, bleeding risk, creatinine clearance and proportion of patients with concomitant illnesses compared with patients initiated on VKAs. Treatment convenience was perceived to be significantly better with dabigatran versus VKAs at visits 2 and 3 (p=0.0423 and 0.0287, respectively). Treatment satisfaction was significantly better with dabigatran compared with VKAs at visit 3 (p=0.0300).
CONCLUSION: In this study, dabigatran is associated with better patient perception in terms of treatment convenience and satisfaction compared with VKAs when used for stroke prevention in newly diagnosed NVAF patients from South East Asia and South Korea.
TRIAL REGISTRATION NUMBER: NCT02849509.
PLAIN LANGUAGE SUMMARY: Patient satisfaction with dabigatran versus VKAs in South East Asia. Patients with atrial fibrillation are at high risk of stroke and require anticoagulants for stroke prevention. Two such anticoagulants are dabigatran and VKAs. We wanted to compare the extent of satisfaction and treatment convenience among newly diagnosed patients with atrial fibrillation from the South East Asian region when they were given either dabigatran or VKAs. Consenting patients filled out a standardised questionnaire called the PACT-Q2 over three visits after they were started on either dabigatran (591 patients) or VKAs (343 patients). We found that satisfaction and convenience were significantly higher when patients received dabigatran than when they received VKAs.
PURPOSE: This scoping review aims to describe the effect of lipid-based formulations on the oral bioavailability of herbal compounds.
METHODS: A systematic search was conducted across three electronic databases (Medline, Embase and Cochrane Library) between January 2010 and January 2021 to identify relevant studies. The articles were rigorously screened for eligibility. Data from eligible studies were then extracted and collated for synthesis and descriptive analysis using Covidence.
RESULTS: A total of 109 studies were included in the present review: 105 animal studies and four clinical trials. Among the formulations investigated, 50% were emulsions, 34% lipid particulate systems, 12% vesicular systems, and 4% were other types of lipid-based formulations. Within the emulsion system classification, self-emulsifying drug delivery systems were observed to produce the best improvements in oral bioavailability, followed by mixed micellar formulations. The introduction of composite lipid-based formulations and the use of uncommon surfactants such as sodium oleate in emulsion preparation was shown to consistently enhance the bioavailability of herbal compounds with poor oral absorption. Interestingly, the lipid-based formulations of magnesium lithospermate B and Pulsatilla chinensis produced an absolute bioavailability greater than 100% indicating the possibility of prolonged systemic circulation. With respect to chemical conjugation, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was the most frequently used and significantly improved the bioavailability of its phytoconstituents.
CONCLUSION: Our findings suggest that there is no distinct lipid-based formulation superior to the other. Bioavailability improvements were largely dependent on the nature of the phytoconstituents. This scoping review, however, provided a detailed summary of the most up-to-date evidence on phytoconstituents formulated into lipid preparations and their oral bioavailability. We conclude that a systematic review and meta-analysis between bioavailability improvements of individual phytoconstituents (such as kaempferol, morin and myricetin) in various lipid-based formulations will provide a more detailed association. Such a review will be highly beneficial for both researchers and herbal manufacturers.