Aza-BODIPY-based phototheranostic nanoagent for tissue oxygen auto-adaptive photodynamic/photothermal complementary therapy

Tumor oxygen spatial heterogeneity is a critical challenge for the photodynamic inhibition of solid tumors.Development of an intelligent nanoagent to initiate optimal therapeutics according to the localized oxygen levels is an effective settlement.Herein,we report an activatable nanoagent(BDP-Oxide nanoparticles(NPs))to enable the oxygen auto-adaptive photodynamic/photothermal complementaly treatment.Upon the nanoagent accumulated in the tumor region,the low extracellular pH could trigger the disassociation of the nanoagent to release the phototheranostic agent,BDP-Oxide,which will subsequently afford the fluorescence imaging-guided photodynamic oxidation after it gets into the outer oxygen-rich tumors.Along with the penetration deepening in the solid tumor,furthermore,BDP-Oxide could be reduced into BDP by the cytochrome P450(CYP450)enzymes activated in the low oxygen tension regions of inner hypoxic tumors,which will switch on the photothermal and photoacoustic effects.Overall,the BDP-Oxide NPs-enabled photodynamic/photothermal complementary therapy significantly suppressed the solid tumor growth(inhibition rate of 94.8%).This work proposes an intelligent platform to address the oxygen partial pressure for the optimization of cancer phototherapeutics.

Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the fifth most common type of cancer and the fourth leading cause of cancer-related deaths in the world.HCC has a reported recurrence rate of 70%-80%after 5 years of follow-up.Controlling tumor recurrence is the most critical factor associated with HCC mortality.Conventional salvage therapies for recurrent HCC include re-hepatectomy or liver transplantation,transcatheter arterial chemoembolization,Y-90,target therapy,and immunotherapy;however,these conventional treatment modalities have yet to achieve consistently favorable outcomes.Meanwhile,previous studies have demonstrated that conventional therapies in combination with traditional Chinese medicine(TCM),acupuncture,moxibustion or dietary supplements could notably benefit patients with HCC recurrence by strengthening and augmenting the overall management strategy.However,systemic reviews related to the interactions between complementary therapies and conventional therapy in recurrent HCC are limited.In this review,we discuss the molecular mechanisms underlying the functions of complementary therapies for recurrent HCC,which include augmenting the local control to improve the congestion status of primary tumors and reducing multicentric tumor occurrence via inducing autophagy,apoptosis or cell cycle arrest.TCM and its derivatives may play important roles in helping to control HCC recurrence by inhibiting epithelial-mesenchymal transition,migration,invasion,and metastasis,inhibiting cancer stem cells,and ameliorating drug resistance.

Non-pharmacological management for chemotherapy-induced nausea and vomiting in patients with cancer:a scoping review

Objective:This review aimed to map and summarize published studies that tested non-pharmacological management for chemotherapyinduced nausea and vomiting(CINV).Methods:We searched for eligible studies in 5 electronic databases and screened the retrieved studies using the inclusion and exclusion criteria.Data were then collated according to the types of interventions,measurement tool,and outcomes.Results:The search yielded 2343 records,of which 11 were included.Four categories of non-pharmacological CINV management were made;manipulative and body-based therapy(n=5 studies);mind–body therapy(n=3 studies);biologically based practice(n=1 study),and energy therapy(n=2 studies).Seven different scales were used to measure CINV.Nine studies repor ted improvement in CINV.Conclusions:This scoping review demonstrates the breadth of non-pharmacological management to address CINV.Various types of CINV scales were used to measure CINV severity.The management and scale can be utilized to improve nursing care,par ticularly in cancer care.

Using complementary and alternative medicines to prevent and treat pressure ulcers: a systematic review

Background:Pressure ulcers are skin lesions generated by ischemic conditions caused by pressure on soft tissues.Several studies have investigated complementary and alternative medicine(CAM)as preventative and treatment measures for pressure ulcers.Therefore,we systematically reviewed the CAM literature in preventing and treating pressure ulcers.Methods:All clinical trial studies which used CAM were included.We searched different databases,including Scientific Information Database,Irandoc,Google Scholar,PubMed,Medline,Scopus,Cochrane Library,Embase,and Science Direct.The following keywords were used:“complementary and alternative medicine-CAM”,“integrative medicine”,“traditional medicine”,“pressure ulcer”,“bedsore”,“pressure sore healing”,and“prevention”.A Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2015 checklist was used to perform analyses.Results:After screening,35 studies were selected.Our investigations suggested that honey,medicinal plants,such as resin salve,Angelica dahurica,Aloe vera,fruits,herbal oils,a combination of several traditional medicine methods,sheepskin,maggot therapy,massage,charcoal,and acupuncture were the most common CAM methods.Conclusion:CAM strategies can prevent and treat pressure ulcers.They reduce wound size,exudate and necrotic tissue levels,inflammation,pain,bleeding,and infections.

Why meta-analyses are important for complementary and alternative medicine research

Complementary and alternative medicine(CAM) is defined as a group of interventions that are not generally considered part of conventional medicine. This definition already implies that CAM interventions are often not systematically studied; and the research evidence from single trials on CAM is often limited by small sample sizes, unclear methodology, and inadequate statistics. As a result, both, significant and insignificant results are oftenhard to interpret based on single trials. Summarizing the evidence from single CAM trials, qualitative systematic reviews still have to deal with the same problems as individual trials as they can only rely on the original reports. Thus, effects of CAM interventions are often underestimated or overestimated based on single trials or qualitative systematic reviews. While meta-analyses still are limited by the methodological shortcomings of the included studies, a well-conducted meta-analysis can deal with two common problems of CAM trials: inadequate statistics that rely on within-group comparisons and small underpowered sample sizes. Although large and high quality trials are urgently needed for most CAM interventions, funding often is limited. Until higher quality research is available, meta-analyses provide a useful tool to investigate the actual level of evidence of currently published CAM trials. This editorial presents examples of meta-analyses in the field of CAM and discusses how they contribute to the consolidation of evidence.

A Review for Existing Complementary and Alternative Medical Therapies for Autism Spectrum Disorder

Autism Spectrum Disorder(ASD)has always been a frustrating disability for families and no official effective medical interventions has been found to cure this disorder yet.With more attention from the general public both nationally and internationally,more and more families and therapists showed preference to implement complementary and alternative medical(CAM)therapies.This review aims to provide more information about potential CAM that has been applied and their effectiveness.

Nonpharmacological pain management practices among nurses working in multiple centers in Saudi Arabia: A cross-sectional study

Objective:The aim of the study was to investigate the prevalence,and determinants,of nonpharmacological pain management practices among nurses in multiple settings.Materials and Methods:A cross-sectional examination was conducted involving 324 nurses from 16 hospitals in Hai’l,Saudi Arabia.Participants completed a self-reported survey utilizing established tools to assess the frequency of nonpharmacological pain management interventions utilization and identify associated barriers.Data analysis was performed using SPSS version 29.0.Results:Nonpharmacological pain management practices were found to be utilized“sometimes,”with a score of 2.89±0.48.Commonly employed techniques included placing patients in comfortable positions and providing a tranquil environment.Gender was the sole demographic factor significantly affecting the use of these techniques(P<0.001),with female nurses demonstrating higher utilization.Barriers to implementation varied based on the hours of recent pain management education(P=0.004),with prevalent barriers including nurse shortages,multiple responsibilities,heavy workloads,and nurse fatigue.Conclusion:The study reveals moderate utilization of nonpharmacological pain management approaches,primarily focusing on patient positioning and creating a calm environment.Female nurses exhibited higher adoption rates of these techniques.Barriers to implementation,such as nurse shortages and heavy workloads,were influenced by recent pain management education.Consequently,enhancing education and fostering supportive work environments are crucial for surmounting these barriers and promoting pain management awareness among nurses.

Current complementary and alternative therapy for gastroesophageal reflux disease

Gastroesophageal reflux disease(GERD)is a widely prevalent gastrointestinal disorder,affecting13.3%of the global population.There are shortages and limitations of current GERD treatment modalities,and complementary and alternative therapy(CAT)is a promising option to fill in the gap.Dietary and lifestyle modifications might play an important and complementary role in alleviating GERD symptoms.Traditional Chinese medicine and brain–gut behavior therapy,particularly transcutaneous electrical acustimulation and diaphragmatic breathing therapy were shown to be useful adjuncts or alternatives in treating GERD.CAT may help to relieve GERD symptoms,minimize medication dosage,and slow the demand for surgery.The aim of this review was to summarize the existing evidence of some common CATs in treating symptomatic GERD,including dietary modification,lifestyle change,traditional Chinese medicine,and brain–gut behavior therapy.

Complementary and alternative medicine on cognitive defects and neuroinflammation after sepsis

Sepsis-associated encephalopathy(SAE)is a common manifestation of sepsis,ranging from mild confusion and delirium to severe cognitive impairment and deep coma.SAE is associated with higher mortality and long-term outcomes,particularly substantial declines in cognitive function.The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain,a disrupted blood–brain barrier,oxidative stress,neurotransmitter dysfunction,and severe microglial activation.Increasing evidence suggests that complementary and alternative medicine,especially Traditional Chinese Medicine(TCM),is favorable in alleviating cognitive decline after sepsis.Here,we summarized the studies of traditional herbal remedies,TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.

Efficacy and safety of mild-warm moxibustion in treating diarrhea-predominant irritable bowel syndrome(spleen deficiency and dampness excess syndrome):a study protocol for a randomized controlled trial

1Background:Irritable bowel syndrome(IBS)is a disorder of bowel function,and diarrhea-predominant irritable bowel syndrome(IBS-D)is the most common.The current treatment for IBS-D is focused on improving patients’gastrointestinal-related symptoms,but there are limitations such as unstable effects and adverse drug reactions.Acupuncture and moxibustion exerts advantages in treating IBS-D.They include several forms,of which moxibustion is one of the most commonly used.And moxibustion is a common way used in treating IBS-D,but there is a lack of relevant evidence-based medical research data.This protocol aims to compare the efficacy of moxibustion(mild-warm moxibustion)in treating IBS-D(spleen deficiency and dampness excess syndrome)with the first-line treatment.Methods:In this prospective,parallel,randomized controlled trial(RCT)protocol,patients will be randomly allocated for 4-week treatment or control therapies and then 4-week follow-up in both groups.We will use Irritable Bowel Syndrome-Symptom Severity Scale(IBS-SSS)score,Irritable Bowel Syndrome-Quality of Life(IBS-QOL)score,serum brain-gut peptide levels,and traditional Chinese medicine(TCM)syndrome scale score to produce more evidence on IBS-D treatment with moxibustion.Finally,we will use SPSS 22.0 software to statistically analyze the data.Discussion:Mild-warm moxibustion is a complementary alternative therapy that fits with the pathogenesis of IBS-D.We hope to see more clinical evidence for mild-warm moxibustion against IBS-D that this RCT supported.

Observations from the Working Group Peritoneal Carcinosis

The aim of this report was to describe the feasibility, overall survival and quality of life of combining multimodal therapy with a complementary therapy concept called LOTUS Care Cure program. The peritoneal carcinomatosis (PC) working group described their observations on the combination of multimodal therapy with a complementary therapy concept based on 132 patients with different cancer entities with suspected PC. PC was not confirmed by laparoscopy in 32.5% of the patients included in the working group of patients with suspected PC. Patient compliance and the feasibility were high. For Ki67, there is a cut-off at 45% with a slower progression at <45% and a faster progression of the disease at >45%. The higher the Karnofsky index, the more improved the therapy and tolerability, with a cut-off of 80%. Overall, 72.0% of patients died. The median survival time in the overall population was 3.74 years (95% CI, 2.57 to 4.91) with a sharp decline in the first 16 weeks. The quality of life of patients can be improved with the implementation of the complementary LOTUS Care Cure Project. Overall, the therapy of PC requires a multi-professional team of therapists and a multimodal therapy concept. The multimodal concept together with the Lotus Care Cure project shows very good feasibility with high compliance and ultimately leads to better and low-risk patient care.

Visualizing the intellectual structure and recent research trends of diabetic retinopathy

AIM:To analyze the intellectual structure and recent research trends in diabetic retinopathy(DR)and unearth potential knowledge.METHODS:English DR publication included in this study was exported from the Web of Science Core Collection,and Chinese DR publication was exported from China National Knowledge Infrastructure from the establishment time of the database to 2019.CiteSpace and Microsoft Excel were used to visually analyze DR research,including analysis of the number of publications,highly cited publication analysis,spatial distribution analysis,and keyword co-occurrence analysis.RESULTS:A total of 23795 English studies and 11577 Chinese studies,including 2089 studies related to traditional Chinese medicine(TCM),were obtained.The data suggested the following:1)The number of English and Chinese DR publications increased over time,and the growth rate of English publications was relatively fast.2)The distribution of international scholars and institutions was close,while the distribution was scattered in China.Shanghai Jiao Tong University has the largest number of publications.Tien-Yin Wong was the core author with the largest number of publications.England and the United States are the core of international DR research cooperation.3)Optical coherence tomography and risk factors are recent international research hot spots and trends.The difference is that TCM is a recent research trend under DR in China.CONCLUSION:DR has drawn an increasing amount of attention worldwide.The focus of research in this field has shifted from tertiary type DR treatment to secondary prevention strategies which focus on the screening and monitoring of disease progression.The advantages of TCM in the prevention of DR have attracted attention,and it is worth incorporating this with Western medicine to address this challenge.

Acute moderate to severe ulcerative colitis treated by traditional Chinese medicine:A case report

BACKGROUND Ulcerative colitis(UC),also known as chronic nonspecific UC,is an inflammatory bowel disease characterized by diffuse colonic mucosal inflammation.The incidence and prevalence of UC have risen markedly,and the disease seriously affects the quality of life of patients and imposes a great burden on the world health care infrastructure and economy.CASE SUMMARY Case I describes a 34-year-old female who came to see a doctor because of repeated abdominal pain,diarrhoea and purulent blood for 2 mo.This patient had UC with an initial onset,an active stage and a wide range of lesions.After the poor effect of sulfasalazine and mesalazine,the patient’s condition gradually deteriorated,her abdominal pain and bloody stools continued,and anemia occurred.She began treatment with the Chinese medicine Guizhi Dahuang decoction,which was taken orally twice a day,200 mL each time.After 6 mo of treatment,abdominal pain,diarrhoea,bloody stool and other symptoms disappeared.No abnormality was found by repeat electronic enteroscopye,and the anemia was corrected.The patient’s condition did not recur after nearly 4 years of follow-up.CONCLUSION A series of symptoms in this UC patient significantly improved with the administration of traditional Chinese medicine.

Labor Pain Treated with Acupuncture or Acupressure

Opioid-dependent women have an 80% to 90% unintended pregnancy rate, almost double the overall unintended pregnancy rate: 40% globally and 51% in north America. The prescription drug abuse milieu increases the possibility opioid abusing laboring patients. In 2012, neonatal abstinence syndrome occurred in 5.8 per 1000 hospital births. Non-pharmacological labor pain management (NPLPM) is especially recommended for laboring patients with a history of substance abuse. Therefore, literature review was performed to elucidate the efficacy and safety of acupuncture, noninvasive electro-acupuncture (EA), and acupressure in labor pain management. Compared to standard intrapartum controls, bilateral EA at JiaJin or Sanyinjiao significantly reduced visual analog scale (VAS) pain scores 30-minutes post intervention (p < 0.01) and Stage 1 active phase labor length (p < 0.05). EA achieves shorter Stage 2 labor than patient-controlled epidural analgesia (p = 0.05);and 10-point lower VAS pain scores and reduced cesarean delivery rate than no-analgesia controls, p < 0.05. Current evidence indicates that EA should have a role in NPLPM, and that acupressure may have a role in NPLPM. Nevertheless, future RCTs could strengthen the argument for increased EA and acupressure use in NPLPM.

Effectiveness and Safety Evaluation of Chinese Medicine in Treatment of Metastatic Colorectal Cancer after Chemotherapy Failure: Protocol of a Prospective Multicenter Cohort Study

Background:Colorectal cancer(CRC)is the second most common cause of cancer-related deaths and has the third highest incidence in the world.Almost half of the patients with CRC have metastases at the time of diagnosis.However,the treatment for patients with metastatic CRC that progresses after approved conventional chemotherapy is still controversial.Chinese medicine(CM)has unique characteristics and advantages in treating metastatic CRC.Objective:To assess the effectiveness and safety of CM in patients with metastatic CRC after failure of conventional chemotherapy.Methods:The study is a multicenter prospective cohort study.A total of 384 patients with documented metastatic CRC after failure of conventional chemotherapy will be included from 9 hospitals at Beijing,Shanghai,Nanjing,and Guizhou,and assigned to three groups according to paitents'wishes:(1)integrated Chinese and Western medicine(ICM)group receiving CM herbal treatment combined with Western medicine(WM)anti-tumor therapy,(2)Chinese medicine(CM)group receiving only CM herbal treatment,and(3)WM group receiving only WM anti-tumor therapy.The primary endpoint is the overall survival(OS).Secondary endpoints include the progression free survival(PFS),quality of life(QOL)assessed by the Functional Assessment of Cancer Therapy-Colorectal(FACT-C)questionnaire,tumor control,and CM symptom score.Discussion:This prospective study will assess the effectiveness and safety of CM in treating metastatic CRC after conventional chemotherapy failure.Patients in the ICM group will be compared with those in the WM group and CM group.If certified to be effective,national provision of CM treatment in metastatic CRC will probably be advised.(Registration No.NCT02923622).

Complementary and alternative medicine use in Iranian patients with diabetes mellitus

OBJECTIVE： There is increasing interest in complementary and alternative medicine generally, and especially by those affected by chronic diseases, such as diabetes mellitus. We aimed to determine the prevalence and pattern of complementary and altemative medicine use among patients suffering from diabetes mellitus in Shiraz, southern Iran. Another objective was to explore associated factors for use of complementary and alternative medicine among patients with diabetes mellitus. METHODS： A 19-item semi-structured questionnaire （open- and close-ended） was administered to 239 patients with diabetes mellitus in this cross-sectional study. It was carried out in two outpatient diabetes clinics affiliated with the Shiraz University of Medical Sciences, Shiraz, Iran. RESULTS： One hundred and eighty patients （75.3%） used at least one type of complementary and alternative medicine in the last year prior to the interview. Patients with diabetes mellitus who were living in a large family （〉 5 members）, not taking insulin, and believed that complementary and alternative medicine have synergistic effects with conventional medicine, were independently and significantly （P values： 0.02, 0.04, and 0.01, respectively） more likely to use complementary and alternative medicine. Most of the users （97.7%） reported use of herbal preparations, and 89.4% of users did not change their medication, neither in medication schedule nor its dosage. CONCLUSION： The use of complementary and alternative medicine, especially herbal remedies, is popular among diabetes patients in Shiraz, Iran. This use is associated with patients＇ family size, type of conventional medications and their view about concomitant use of complementary and conventional medicine.

Use of complementary and alternative medicine among Thai patients with type 2 diabetes mellitus

OBJECTIVE： Patients with diabetes commonly use complementary and alternative medicine （CAM）. Little is known about types and factors related to CAM use in patients with diabetes in Thailand. This study aimed to examine types and factors that were associated with CAM use in Thai diabetic patients.METHODS： A cross-sectional study of diabetic patients being treated in four primary healthcare units and two secondary hospitals in the north of Thailand was conducted. A questionnaire was used to collect data. Frequency, percentage, and Chi-square test were used to describe or analyze data.RESULTS： The three most common types of CAM used by samples were Daode Xinxi （a modified version of Taichi）, prayer and meditation. Women were more likely to use CAM than men （χ^2=5.038, P=0.018）. Patients aged between 40 and 69 years were more likely to use CAM than those aged younger than 40 or older than 69 years （χ^2=11.041, P=0.026）. Farmers were more likely to use CAM than those with other careers （χ^2=19.248, P=0.007）. Diabetes patients whose time since diagnosis was between 1 and 10 years were more likely to use CAM than those with a longer elapsed time since diagnosis （χ^2= 8.407, P = 0.038）. Marital status, religion, education, health insurance type and conventional treatment approaches were not associated with CAM use in diabetic patients.CONCLUSION： The most common type of CAM used by Thai patients with diabetes was mind and body practice. CAM use was significantly associated with gender, age, career and duration of diabetes However, marital status, religion, education, health insurance types and conventional regimen for diabetics were not associated with CAM use.

Knowledge, attitude and practice of patients with type 2 diabetes mellitus towards complementary and alternative medicine

OBJECTIVE： The use of complementary and alternative medicine（CAM） is relatively common among patients with type 2 diabetes mellitus（T2DM） around the world. Like many other countries, Saudi Arabia has a high incidence of T2DM, and incorporates the use of CAM in its treatment. This study explores the knowledge, attitude and practice（KAP） of CAM therapies among patients with T2DM and explores the relationships between sociodemographics and the KAP of CAM modalities. METHODS： This is a hospital-based, observational, cross-sectional study that selected 302 outpatients with T2DM, from Diabetic Center of King Salman bin Abdul-Aziz Hospital, in Riyadh city, in May 2014. Patients were interviewed using a predesigned questionnaire. RESULTS： The mean age of patients was（51.6 ± 10.6） years and 43.4% of them were males. The prevalence of CAM practices was 30.5%; 30.39% of them used herbs, 20.58% used wet cupping and 17.64% used nutritional supplements and other therapies. The factors found to predict the use of CAM therapies among patients with T2DM were： age above 51 years, unemployment and the participants’ knowledge about the effectiveness of CAM products. CONCLUSION： This preliminary study estimated the prevalence of CAM use, revealed positive attitude towards CAM and found three significant predictors of CAM use among patients with T2DM, which is consistent with regional data. A community-based research with a larger sample that targets T2DM population is needed in Saudi Arabia.

Perceptions of traditional,complementary and alternative medicine among conventional healthcare practitioners in Accra,Ghana:Implications for integrative healthcare

OBJECTIVE： Integrative medicine refers to ongoing efforts to combine the best of conventional and evidence-based complementary therapies. While this effort for collaboration is increasing, traditional complementary and alternative medicine （TM-CAM） remains poorly integrated into the current healthcare system of Ghana. At present, it is not clear if practitioners of mainstream medicine favor integrative medicine. The present study, therefore, sought to explore the perceptions of conventional healthcare professionals on integrative medicine. METHODS： A qualitative design composed of semi-structured interviews was conducted with 23 conventional healthcare professionals comprising pharmacists, physicians, nurses and dieticians from two quasi-government hospitals in Accra, Ghana. RESULTS： Participants＇ knowledge of TM-CAM was low, and although they perceived alternative medicine as important to current conventional healthcare in Ghana, they expressed anxieties about the potential negative effects of the use of TM-CAM. This paradox was found to account for the low levels of use among these professionals, as well as the low level of recommendation to their patients. The practitioners surveyed recommended that alternative medicine could be integrated into mainstream allopathic healthcare in Ghana through improving knowledge, training as well as addressing concerns of safety and efficacy. These findings are discussed under the themes： the knowledge gap, the paradox of TM-CAM, experience of use and prescription, and guided integration. We did not observe any differences in views among the participants. CONCLUSION： The conventional healthcare professionals were ready to accept the idea of integrative medicine based on knowledge of widespread use and the potential role of TM-CAM products and practices in improving healthcare delivery in the country. However, to achieve an institutional integration practitioners＇ understanding of TM-CAM must be improved, with specific attention to issues of safety, regulation and evidence-based practice of TM-CAM products and services in Ghana.

The use of complementary and alternative medicine by individuals with features of metabolic syndrome

OBJECTIVE： To compare the use of complementary and alternative medicine （CAM）, including dietary supplements, by individuals with and without features of metabolic syndrome （FeMS）. METHODS： Using a cross sectional study design, information was obtained by self-administered questionnaires from 300 university individuals. FeMS was defined as any individuals self-reporting at least one of the clinical diagnoses of diabetes, hypertension, hyperlipidemia, or obesity. Finally, two categories were created for cross tabulation, and individuals with and without FeMS were compared. RESULTS： Of the 192 individuals completing the study, 39% （n=76） were currently using or had used CAM therapies in the past 12 months. Individuals with FeMS （n=54, 28%） were more likely （P〈0.05） to use different types of CAM therapies, in particular dietary and herbal supplements, aromatherapy and massage therapy compared to individuals without FeMS （n=138, 72%）. CONCLUSION： Individuals with FeMS were more likely to use CAM, particularly supplements. Doctors need to properly inquire about and understand their patients＇ supplement use, especially if CAM therapies are used in coniunction with conventional medications.