A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications.

There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.

The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.

Synergistic immunosuppressive effect of hispidulin and nepetin mixtures on human T lymphocytes.

BACKGROUND: Clerodendrum petasites S. Moore predominantly contains hispidulin (His) and nepetin (Nep) which are immunosuppressive potentials. Although the effect of individual compounds was previously confirmed, a cumulative suppression of these flavonoid mixtures is unknown. This study thus investigated their inhibitory effects and cytotoxicity on T cells by using His:Nep ratios following a naturally occurring dose (3:1) and optimized doses (1:1 and 1:3). MATERIALS AND METHODS: Anti-CD3/28 stimulated peripheral blood mononuclear cells were treated with individual compounds and their mixtures. Changes in early cell activation markers in activated T cells and apoptosis were analyzed by a flow cytometer. RESULTS: Mixtures at 3:1 suppressed CD69 and CD25 expression in CD4+ and CD8+ T cells in a dose-dependent manner. At the highest concentration of 200 µM His + 66.7 µM Nep, over 90% inhibition was observed for CD25 expression in CD4+ and CD8+ T cells, whereas a lesser effect was observed for CD69 expression. A dose-dependent inhibition was still observed when using 1:1 and 1:3 ratios. Interestingly, 80-97% inhibition were observed in CD69 and CD25 expression without inducing cell death after treated with the highest doses of each ratio (66.7 µM His + 200 µM Nep and 200 µM His + 200 µM Nep). These mixtures were also exhibited a better suppression than individual compounds. CONCLUSIONS: The optimized mixture of His and Nep at 66.7:200 µM is suggested for further study due to a greater suppressive effect than a single compound or a naturally-occurring dose.

Tea Plant (Camellia sinensis): A Current Update on Use in Diabetes, Obesity, and Cardiovascular Disease.

The tea plant (C. sinensis) has traditionally been consumed worldwide as "tea" for its many health benefits, with the potential for the prevention and therapy of various conditions. Regardless of its long history, the use of tea plants in modern times seems not to have changed much, as the beverage remains the most popular form. This review aimed to compile scientific information about the role and action of tea plants, as well as their status concerning clinical applications, based on the currently available evidence, with a focus on metabolic syndrome, mainly covering obesity, diabetes, and cardiovascular disease. It has been recognized that these diseases pose a significant threat to public health, and the development of effective treatment and prevention strategies is necessary but still challenging. In this article, the potential benefits of tea plants and their derived bioactive components (such as epigallocatechin-3-gallate) as anti-obesity, anti-diabetic, and anti-cardiovascular agents are clearly shown and emphasized, along with their mechanisms of action. However, according to the status of the clinical translation of tea plants, particularly in drug development, more substantial efforts in well-designed, randomized, controlled trials are required to expand their applications in treating the three major metabolic disorders and avoiding the toxicity caused by overconsumption.

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases.

Polyphenols are a family of naturally occurring organic compounds, majorly present in fruits, vegetables, and cereals, characterised by multiple phenol units, including flavonoids, tannic acid, and ellagitannin. Some well-known polyphenols include resveratrol, quercetin, curcumin, epigallocatechin gallate, catechin, hesperetin, cyanidin, procyanidin, caffeic acid, and genistein. They can modulate different pathways inside the host, thereby inducing various health benefits. Autophagy is a conserved process that maintains cellular homeostasis by clearing the damaged cellular components and balancing cellular survival and overall health. Polyphenols could maintain autophagic equilibrium, thereby providing various health benefits in mediating neuroprotection and exhibiting anticancer and antidiabetic properties. They could limit brain damage by dismantling misfolded proteins and dysfunctional mitochondria, thereby activating autophagy and eliciting neuroprotection. An anticarcinogenic mechanism is stimulated by modulating canonical and non-canonical signalling pathways. Polyphenols could also decrease insulin resistance and inhibit loss of pancreatic islet ß-cell mass and function from inducing antidiabetic activity. Polyphenols are usually included in the diet and may not cause significant side effects that could be effectively used to prevent and treat major diseases and ailments.

Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy.

Introduction: Despite the availability of new vaccines for SARS-CoV-2, there has been slow uptake and problems with supply in some parts of the world. Hence, there is still a necessity for drugs that can prevent hospitalization of patients and reduce the strain on health care systems. Drugs with sigma affinity potentially provide protection against the most severe symptoms of SARS-COV-2 and could prevent mortality via interactions with the sigma-1 receptor.Areas covered: This review examines the role of the sigma-1 receptor and autophagy in SARS-CoV-2 infections and how they may be linked. The authors reveal how sigma ligands may reduce the symptoms, complications, and deaths resulting from SARS-CoV-2 and offer insights on those patient cohorts that may benefit most from these drugs.Expert opinion: Drugs with sigma affinity potentially offer protection against the most severe symptoms of SARS-CoV-2 via interactions with the sigma-1 receptor. Agonists of the sigma-1 receptor may provide protection of the mitochondria, activate mitophagy to remove damaged and leaking mitochondria, prevent ER stress, manage calcium ion transport, and induce autophagy to prevent cell death in response to infection.

The effectiveness of Bacopa monnieri (Linn.) Wettst. as a nootropic, neuroprotective, or antidepressant supplement: analysis of the available clinical data.

Bacopa monnieri (Linn.) Wettst. has been used in traditional medicine as a drug to enhance and improve memory. In this regard, this study aims to provide B. monnieri's efficacy as a neuroprotective drug and as a nootropic against various neurological diseases. Literatures were collected, following Prisma guidelines, from databases, including Scopus, PubMed, Google Scholar, and Science Direct and were scrutinized using a quality scoring system. Means, standard deviations and 'n' numbers were extracted from the metrics and analyzed. Jamovi computer software for Mac was used to carry out the meta-analysis. The selected studies suggested that the plant extracts were able to show some improvements in healthy subjects which were determined in Auditory Verbal Learning Task, digit span-reverse test, inspection time task and working memory, even though it was not significant, as no two studies found statistically significant changes in the same two tests. B. monnieri was able to express modest improvements in subjects with memory loss, wherein only a few of the neuropsychological tests showed statistical significance. B. monnieri in a cocktail with other plant extracts were able to significantly reduce the effects of Alzheimer's disease, and depression which cannot be solely credited as the effect of B. monnieri. Although in one study B. monnieri was able to potentiate the beneficial effects of citalopram; on the whole, currently, there are only limited studies to establish the memory-enhancing and neuroprotective effects of B. monnieri. More studies have to be done in the future by comparing the effect with standard drugs, in order to establish these effects clinically in the plant and corroborate the preclinical data.

Extensive Characterization of Mesenchymal Stem Cell Marker Expression on Freshly Isolated and In Vitro Expanded Human Adipose-Derived Stem Cells from Breast Cancer Patients.

Variation in numbers and functions of cells in fat tissues may affect therapeutic outcomes and adverse events after autologous fat tissue grafting in postmastectomy breast cancer patients; however, the relevant information regarding cellular components is still incomplete. Phenotypic characterization of heterogeneous cell subsets in stromal vascular fraction (SVF) isolated from fat tissues by flow cytometry was also limited to a combination of few molecules. This study, therefore, developed a polychromatic staining panel for an in-depth characterization of freshly isolated SVF and expanded adipose-derived stem cells (ADSC) from the patients. ADSC were found predominant in SVF (~65% of CD45- cells) with a homogenous phenotype of CD13+CD31-CD34+CD45-CD73+CD90+CD105-CD146- (~94% of total ADSC). Endothelial progenitor cells (EPC) and pericytes were minor (~18% and ~11% of CD45- cells, respectively) with large heterogeneity. Downregulation of CD34 and upregulation of CD105 in ADSC were profound at passage 3, showing a phenotype similar to the classical mesenchymal stem cells from the bone marrow. Results from this study demonstrated that fat tissue collected from patients contains ADSC with a highly homogenous phenotype. The in vitro culture of these cells maintained their homogeneity with modified CD34 and CD105 expression, suggesting the expansion from a single population of ADSC.

The inappropriate use of proton pump inhibitors during admission and after discharge: a prospective cross-sectional study.

Background Proton pump inhibitors are often inappropriately prescribed during hospital admission and after discharge. The inappropriate prescription may be associated with increased and unnecessary healthcare costs. Objective To determine the prevalence of inappropriate prescription of proton pump inhibitors during hospital admission and after discharge at Thailand's largest national tertiary referral center. Setting Medicine wards at Siriraj Hospital (Bangkok, Thailand) during September 2016 to September 2017. Method This prospective observational cross-sectional study in hospitalized patients who were prescribed, or who were already taking proton pump inhibitors. Medical records were reviewed to determine whether proton pump inhibitors were prescribed at discharge and at the 1-month follow-up. Main outcome measure Prevalence of inappropriate prescription of proton pump inhibitors during hospital admission and after discharge, indication of inappropriate prescription. Results Two hundred and sixty-five patients (mean age: 65.8 ± 18.3 years, 50.9% men) were included. Approximately half of patients had proton pump inhibitor treatment initiated in the hospital, and the other 50.6% started treatment earlier. Among all patients, 50.6% were inappropriately prescribed proton pump inhibitors, in which 79.1% resulted from invalid indications. Fifty-two percent and 47.3% of patients who were prescribed proton pump inhibitors at discharge and at the 1-month follow-up had no indications for them. Gastrointestinal ulcer prophylaxis in low-risk patients was the most commonly observed incorrect indication. Aspirin (p = 0.030) and corticosteroids (p = 0.038) were both found to be significantly associated with the inappropriate prescription of proton pump inhibitors. The estimated cost of inappropriate use among inpatients and outpatients was $118,659 and $214,663 per year, respectively. Conclusion Proton pump inhibitors are excessively and inappropriately prescribed during hospital admission and after discharge in Thailand. The cost of this overprescribing is excessive and needs to be controlled.

Immunosuppressive effect of hispidulin in allergic contact dermatitis.

BACKGROUND: Long-term use of most immunosuppressants to treat allergic contact dermatitis (ACD) generates unavoidable severe side effects, warranting discovery or development of new immunosuppressants with good efficacy and low toxicity is urgently needed to treat this condition. Hispidulin, a flavonoid compound that can be delivered topically due to its favorable skin penetrability properties, has recently been reported to possess anti-inflammatory and immunosuppressive properties. However, no studies have investigated the effect of hispidulin on Th1 cell activities in an ACD setting. METHODS: A contact hypersensitivity (CHS) mouse model was designed to simulate human ACD. The immunosuppressive effect of hispidulin was investigated via ear thickness, histologic changes (i.e., edema and spongiosis), and interferon-gamma (IFN-γ) gene expression in 1-fluoro-2,4-dinitrobenzene (DNFB)-sensitized mice. Cytotoxicity, total number of CD4+ T cells, and percentage of IFN-γ-producing CD4+ T cells were also investigated in vitro using isolated CD4+ T cells from murine spleens. RESULTS: Topically applied hispidulin effectively inhibited ear swelling (as measured by reduction in ear thickness), and reduced spongiosis, IFN-γ gene expression, and the number of infiltrated immune cells. The inhibitory effect of hispidulin was observed within 6 h after the challenge, and the observed effects were similar to those effectuated after dexamethasone administration. Hispidulin at a concentration up to 50 µM also suppressed IFN-γ-producing CD4+ T cells in a dose-dependent manner without inducing cell death, and without a change in total frequencies of CD4+ T cells among different concentration groups. CONCLUSION: The results of this study, therefore, suggest hispidulin as a novel compound for the treatment of ACD via the suppression of IFN-γ production in Th1 cells.

Determination of suppressive effect on human T-cell activation by hispidulin, nepetin, and vanillic acid.

Background: Hispidulin, nepetin, and vanillic acid are phenolic compounds potentially possessing immunosuppressive property, however, no information on their pharmacological effect and cytotoxicity has been investigated on human T lymphocytes.Materials and methods: Human peripheral blood mononuclear cells were stimulated with anti-CD3/28 coated beads and treated with individual compound at different concentrations (50-200 µM). Inhibition of early cell activation and induction of apoptosis were analyzed by flow cytometric technique.Results: At 200 µM, frequencies of CD25 and CD69 in CD4+ and CD8+ T lymphocytes were markedly decreased by hispidulin and nepetin. When lowering to 100 and 50 µM, hispidulin had no effect on the expression of CD69 in CD4+ T cells, whereas nepetin selectively suppressed CD25 and CD69 expressions in CD8+ T cells at 100 µM and only inhibited CD69 in CD8+ T cells at 50 µM. For vanillic acid, no inhibitory effect was observed while cell activation was significantly increased for all treated concentrations. None of these compounds disturbed levels of total apoptotic cells in CD4+ and CD8+ populations.Conclusions: Hispidulin and nepetin, therefore, exhibit dose-dependent inhibitory activity of early T-cell activation without inducing cell death, considering feasible immunosuppressants for inflammation-related diseases. However, vanillic acid has no effect on immunosuppression but shows more potential on immunostimulation.HighlightsImmunosuppressive effects of hispidulin and nepetin on human T cells were studied.Dose-dependent activity for T-cell suppression was found in hispidulin and nepetin.Vanillic acid showed immunostimulating potential rather than immunosuppression.All compounds did not induce cell death.

Clerodendrum petasites S. Moore: The therapeutic potential of phytochemicals, hispidulin, vanillic acid, verbascoside, and apigenin.

Clerodendrum petasites S. Moore has been prescribed in Thai traditional medicine for over 30 years for the treatment of ailments including asthma, inflammation, fever, cough, vomiting, and skin disorders. The phytochemicals from this plant have been identified as phenolic acids, flavones, flavone glycosides, glycosides, phenylpropanoid, and diterpenoid. The pharmacological activities both in vitro and in vivo have mostly been reported from crude extracts and not from pure compounds. This review, therefore, brings together information on the specific phytochemicals found in C. petasites in order to provide a guide to the natural bioactive compounds that are potentially used in medicines together with mechanisms underlying their pharmacological uses. All relevant information was searched for the terms of plant name, naturally-occurring compounds, and traditional uses from reliable databases, such as PubMed, Science Direct and Google Scholar, along with Thai traditional medicine textbooks. There was no specific timeline set for the search and this review selected to report only mechanisms studied by using standard compounds for their biological activities. Four dominant compounds comprising hispidulin, vanillic acid, verbascoside, and apigenin, have robust evidence to support their medical effects. Hispidulin was discovered to be possibly responsible for the treatment of cancer, osteolytic bone diseases, and neurological diseases. Other compounds were also found to tentatively support the uses in inflammation and neurological diseases. C. petasites extracts may provide an option as complimentary medicine, and or for the pharmacological development of new drugs derived from the phytochemicals found within.

Determination of cell expansion and surface molecule expression on anti-CD3/28 expanded CD4+ T cells.

CD4+ T cell immunotherapy has potential for treatment in HIV-infected patients. A large number of expanded CD4+ T cells and confirmation of functional-related phenotypes are required for ensuring the successful outcomes of treatment. Freshly isolated CD4+ T cells from healthy donors were activated with anti-CD3/28-coated magnetic beads at different bead-to-cell ratios and cultured in the absence and presence of IL-2 supplementation for 3 weeks. Fold expansion, cell viability, growth kinetic and lymphocyte subset identities were determined. Data demonstrated that a 1:1 bead-to-cell ratio rendered the highest expansion of 1044-fold with 88% viability and 99.5% purity followed by the 2:1 and 0.5:1 ratios. No significant difference in proliferation and phenotypes was found between non-IL-2 and IL-2 supplementation groups. Several specific surface molecule expressions of the expanded cells including chemokine receptors, adhesion molecules, co-stimulatory molecules, activation molecules, maturation markers, cytokine receptors and other molecules were altered when compared to the unexpanded cells. This optimized expansion protocol using the 1:1 bead-to-cell ratio of anti-CD3/28-coated magnetic beads and culture condition without IL-2 supplementation provided the satisfactory yield with good reproducibility. Specific surface molecule expressions of the expanded cells presented potential roles in proliferation, differentiation, homeostasis, apoptosis and organ homing.

B cell subset alteration and the expression of tissue homing molecules in dengue infected patients.

BACKGROUND: B cells play an essential role during dengue viral infection. While a major expansion of antibody secreting cells (ASCs) was observed, the importance of these increased frequencies of ASCs remains unclear. The alteration of B cell subsets may result from the expression of tissue specific homing molecules leading to their mobilization and distribution to different target organs during acute dengue viral infection. METHODS: In this study, whole blood samples were obtained from thirty pediatric dengue-infected patients and ten healthy children and then stained with fluorochrome-conjugated monoclonal antibodies against CD3, CD14, CD19, CD20, CD21, CD27, CD38, CD45, CD138 and homing molecules of interest before analyzed by polychromatic flow cytometry. B cell subsets were characterized throughout acute infection period. RESULTS: Data shows that there were no detectable differences in frequencies of resting, activated and tissue memory cells, whereas the frequency of ASCs was significantly increased and associated with the lower frequency of naïve cells. These results were found from patients with both dengue fever and dengue hemorrhagic fever, suggesting that such change or alteration of B cells was not associated with disease severity. Moreover, several homing molecules (e.g., CXCR3 and CCR2) were found in ASCs, indicating that ASCs may distribute to inflamed tissues and various organs. CONCLUSIONS: Findings from this study provide insight into B cell subset distribution. Furthermore, organ mobilization according to homing molecule expression on different B cell subsets during the course of dengue viral infection also suggests they are distributed to inflamed tissues and various organs.

Identification of changes in dendritic cell subsets that correlate with disease severity in dengue infection.

Dengue virus (DENV) is the most prevalent arthropod-borne viral disease in humans. DENV causes a spectrum of illness ranging from mild to potentially severe complications. Dendritic cells (DCs) play a critical role in initiating and regulating highly effective antiviral immune response that include linking innate and adaptive immune responses. This study was conducted to comparatively characterize in detail the relative proportion, phenotypic changes, and maturation profile of subsets of both myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in children with dengue fever (DF), dengue hemorrhagic fever (DHF) and for purposes of control healthy individuals. The mDCs (Lin-CD11c+CD123lo), the pDCs (Lin-CD11c-CD123+) and the double negative (DN) subset (Lin-/HLA-DR+/CD11c-CD123-) were analyzed by polychromatic flow cytometry. The data were first analyzed on blood samples collected from DENV-infected patients at various times post-infection. Results showed that the relative proportion of mDCs were significantly decreased which was associated with an increase in disease severity in samples from DENV-infected patients. While there was no significant difference in the relative proportion of pDCs between healthy and DENV-infected patients, there was a marked increase in the DN subset. Analysis of the kinetics of changes of pDCs showed that there was an increase but only during the early febrile phase. Additionally, samples from patients during acute disease showed marked decreases in the relative proportion of CD141+ and CD16+ mDC subsets that were the major mDC subsets in healthy individuals. In addition, there was a significant decrease in the level of CD33-expressing mDCs in DENV patients. While the pDCs showed an up-regulation of maturation profile during acute DENV infection, the mDCs showed an alteration of maturation status. This study suggests that different relative proportion and phenotypic changes as well as alteration of maturation profile of DC subsets may play a critical role in the dengue pathogenesis and disease outcome.

A closed-culture system using a GMP-grade culture bag and anti-CD3/28 coated bead stimulation for CD4+ T cell expansion from healthy and HIV-infected donors.

CD4 immunotherapy is potentially useful in immune reconstitution of CD4+ T cells for HIV-infected patients. Transfusion of anti-CD3/28 expanded CD4+ T cells is also proved to be safe and effective in both SIV-infected macaques and HIV-infected patients. However, there is no such standardized and practical protocol available for cell production in order to use in clinics. This study thus aimed to develop a closed-culture system for in vitro CD4+ T lymphocyte expansion by using a commercially available GMP-grade culture bag and anti-CD3/28 activation. Freshly isolated CD4+ T cells by immunorosette formation from healthy donors and cryopreserved CD4+ T cells from HIV-infected patients with CD4 count over 500 cells/µL were stimulated with anti-CD3/28 coated beads. The activated cells were then expanded in conventional culture flasks and GMP-grade culture bags for three weeks. Fold expansion, cell viability, growth kinetic and phenotypic characters were observed. Results revealed that purified CD4+ T cells from healthy individuals cultured in flasks showed better expansion than those cultured in bags (797-fold and 331-fold, respectively), whereas, their cell viability, growth kinetic and expanded CD4+ T cell purity were almost similar. A large-scale production was also conducted and supported consistency of cell proliferation in the closed-culture system. Frozen CD4+ T lymphocytes from the patients were able to remain their growth function and well expanded with a good yield of 415-fold, 85% viability and 96% purity of CD4+ T cells at the end of a 3-week culture in bags. This developed closed-culture system using culture bags and anti-CD3/28 coated beads, therefore, can achieve a large number of expanded CD4+ T lymphocytes with good reproducibility, suggesting a promising protocol required for adoptive immunotherapy.

Impact of Vaccination on Distribution of T Cell Subsets in Antiretroviral-Treated HIV-Infected Children.

Antiretroviral therapy (ART) is generally prescribed to patients with human immunodeficiency virus (HIV) infection with vaccination introduced to prevent disease complications. However, little is known about the influence of immunization on T cell subsets' distribution during the course of infection. This study aims to identify the impact of viral replication and immunization on naïve, effector, effector memory, and central memory T cell subpopulations in ART-treated HIV-infected children. Fifty patients were recruited and injected intramuscularly with influenza A (H1N1) 2009 vaccine on the day of enrollment (day 0) and day 28. Blood samples were collected for pre- and postvaccination on days 0 and 56 for analyzing T cell phenotypes by flow cytometry. Phenotypes of all T cell subsets remained the same after vaccination, except for a reduction in effector CD8+ T cells. Moreover, T cell subsets from patients with controllable viral load showed similar patterns to those with virological failure. Absolute CD4 count was also found to have a positive relationship with naïve CD4+ and CD8+ T cells. In conclusion, vaccination and viral replication have a little effect on the distribution of T cell subpopulations. The CD4 count can be used for prediction of naïve T cell level in HIV-infected patients responding to ART.

Topical formulation and dermal delivery of active phenolic compounds in the Thai medicinal plant--Clerodendrum petasites S. Moore.

PURPOSE: To develop topical formulations of Clerodendrum petasites S. Moore (CP), and to optimize the skin permeability and topical bioavailability of the active phenolic compounds therein. METHODS: The skin uptake and delivery of active compounds from two formulations, an oil-in-water cream and a lotion (both containing 10% w/w CP extracts), were examined (a) invitro using pig skin, and (b) invivo in human volunteers. Stratum corneum (SC) was collected by tape stripping and the compounds were detected and quantified by high performance liquid chromatography coupled with either mass spectrometry (HPLC-MS) or ultraviolet and photodiode array (HPLC-UV-PDA) detection. RESULTS: From the invitro results, vanillic acid, verbascoside, nepetin and hispidulin, were chosen as potential phenolic actives for topical delivery optimization from the formulations. Invivo, vanillic acid, nepetin and hispidulin were appreciably taken up into the SC within 6h, while verbascoside did not penetrate beyond the most superficial layers. No significant differences in delivery were observed between the two formulations, both of which were well tolerated. CONCLUSIONS: The detected topical absorption of hispidulin, nepetin, and vanillic acid, from the cream and lotion vehicles investigated, suggest that these compounds are potentially active compounds in Thai traditional medicine for the treatment of a wide range of skin diseases.

Characterisation of polyphenolic compounds in Clerodendrum petasites S. Moore and their potential for topical delivery through the skin.

ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendrum petasites S. Moore (CP) has been widely prescribed in Thailand and neighbouring countries for both oral and topical administration to treat asthma, fever, cough, vomiting and skin diseases, for at least 30 years. However, the nature of the active species remains poorly characterized and there have been no clinical trials concerning the topical delivery of this medicine. The study aims to characterise polyphenolic compounds in the plant, to predict the feasibility of their topical absorption and to test their ability to penetrate the skin. MATERIALS AND METHODS: Identification and quantification of flavonoids and phenolic acid derivatives in an ethanolic extract of the aerial parts of the plant were carried out using high performance liquid chromatography (HPLC) with photodiode array (PDA) and mass spectrometry (MS) detection. Ambiguous isomeric compounds were distinguished by nuclear magnetic resonance (NMR) spectroscopy. The feasibility of the compounds׳ topical permeability was evaluated by predicting their maximum fluxes from their physicochemical properties. The skin penetration of compounds in the plant extract was measured in vitro over 24h. RESULTS: Vanillic acid, verbascoside, 4-coumaric acid, ferulic acid, nepetin, luteolin, apigenin, naringenin, hispidulin, hesperetin and chrysin, were identified in CP. All compounds except apigenin and hispidulin are reported in this species for the first time. Hispidulin is the predominant compound (1.2% w/w in a dried ethanolic extract) followed by nepetin, verbascoside, vanillic acid, and apigenin. Across mammalian skin, hispidulin was percutaneously absorbed within 3h and vanillic acid and nepetin permeated the skin after 6h. These experimental observations were consistent with the predicted maximum fluxes of these compounds calculated from their physicochemical properties. CONCLUSIONS: Many of the phenolic compounds reported in this study are well-known to possess antimicrobial, anti-inflammatory and anti-oxidant activities. The skin permeation studies reported here support traditional topical uses of the plant in skin treatments and are useful for further topical formulation optimisation.