Displaying publications 1 - 20 of 131 in total

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  1. Loo CY, Lee WH, Zhou QT
    Pharm Res, 2023 May;40(5):1015-1036.
    PMID: 37186073 DOI: 10.1007/s11095-023-03520-1
    With the rapid outbreak of respiratory viral infections, various biological (e.g. vaccines, peptides, recombinant proteins, antibodies and genes) and antiviral agents (e.g. ribavirin, palivizumab and valaciclovir) have been successfully developed for the treatment of respiratory virus infections such as influenza, respiratory syncytial virus and SARS-CoV-2 infections. These therapeutics are conventionally delivered via oral, intramuscular or injection route and are associated with several adverse events due to systemic toxicity. The inherent in vivo instability of biological therapeutics may hinder them from being administered without proper formulations. Therefore, we have witnessed a boom in nanotechnology coupled with a needle-free administration approach such as the inhalation route for the delivery of complex therapeutics to treat respiratory infections. This review discussed the recent advances in the inhalation strategies of nanoformulations that target virus respiratory infections.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  2. Wong MH, Sockalingam S, Zain A
    Int J Rheum Dis, 2011 Aug;14(3):e38-41.
    PMID: 21816012 DOI: 10.1111/j.1756-185X.2011.01602.x
    We report a 57-year-old woman with a 20-year history of hepatitis B presenting with progressive proximal lower limb weakness for the previous 1 month. Previous medical history included a pericardial and pleural effusion, of which no cause was found and pulmonary tuberculosis which has been adequately treated. Examination revealed multiple telangiactasia over face and nail beds and bilateral proximal lower limb weakness of power 4/5. Biochemical investigation revealed a raised erythrocyte sedimentation rate of 36 mm/h, elevated creatinine kinase levels (14,363 IU/L) and raised liver enzymes (alanine aminotransferase 445 IU/L, aspartate aminotransferase 606 IU/L) with high hepatitis B virus DNA (1,021,158 copies/mL). Nerve conduction tests and muscle biopsy were consistent with polymyositis. She received entacavir for hepatitis B treatment. Despite treatment with entacavir for 10 weeks, her weakness persisted and prednisolone was added. Upon commencement of prednisolone, her symptoms and biochemical profiles returned to normal.
    Matched MeSH terms: Antiviral Agents/therapeutic use*
  3. Rothan HA, Bahrani H, Shankar EM, Rahman NA, Yusof R
    Antiviral Res, 2014 Aug;108:173-80.
    PMID: 24929084 DOI: 10.1016/j.antiviral.2014.05.019
    Chikungunya virus (CHIKV) outbreaks have led to a serious economic burden, as the available treatment strategies can only alleviate disease symptoms, and no effective therapeutics or vaccines are currently available for human use. Here, we report the use of a new cost-effective approach involving production of a recombinant antiviral peptide-fusion protein that is scalable for the treatment of CHIKV infection. A peptide-fusion recombinant protein LATA-PAP1-THAN that was generated by joining Latarcin (LATA) peptide with the N-terminus of the PAP1 antiviral protein, and the Thanatin (THAN) peptide to the C-terminus, was produced in Escherichia coli as inclusion bodies. The antiviral LATA-PAP1-THAN protein showed 89.0% reduction of viral plaque formation compared with PAP1 (46.0%), LATA (67.0%) or THAN (79.3%) peptides alone. The LATA-PAP1-THAN protein reduced the viral RNA load that was 0.89-fold compared with the untreated control cells. We also showed that PAP1 resulted in 0.44-fold reduction, and THAN and LATA resulting in 0.78-fold and 0.73-fold reductions, respectively. The LATA-PAP1-THAN protein inhibited CHIKV replication in the Vero cells at an EC50 of 11.2μg/ml, which is approximately half of the EC50 of PAP1 (23.7μg/ml) and protected the CHIKV-infected mice at the dose of 0.75mg/ml. We concluded that production of antiviral peptide-fusion protein in E. coli as inclusion bodies could accentuate antiviral activities, enhance cellular internalisation, and could reduce product toxicity to host cells and is scalable to epidemic response quantities.
    Matched MeSH terms: Antiviral Agents/therapeutic use*
  4. Rothan HA, Bahrani H, Mohamed Z, Teoh TC, Shankar EM, Rahman NA, et al.
    PLoS One, 2015;10(5):e0126360.
    PMID: 25970853 DOI: 10.1371/journal.pone.0126360
    Lack of vaccine and effective antiviral drugs against chikungunya virus (CHIKV) outbreaks have led to significant impact on health care in the developing world. Here, we evaluated the antiviral effects of tetracycline (TETRA) derivatives and other common antiviral agents against CHIKV. Our results showed that within the TETRA derivatives group, Doxycycline (DOXY) exhibited the highest inhibitory effect against CHIKV replication in Vero cells. On the other hand, in the antiviral group Ribavirin (RIBA) showed higher inhibitory effects against CHIKV replication compared to Aciclovir (ACIC). Interestingly, RIBA inhibitory effects were also higher than all but DOXY within the TETRA derivatives group. Docking studies of DOXY to viral cysteine protease and E2 envelope protein showed non-competitive interaction with docking energy of -6.6±0.1 and -6.4±0.1 kcal/mol respectively. The 50% effective concentration (EC50) of DOXY and RIBA was determined to be 10.95±2.12 μM and 15.51±1.62 μM respectively, while DOXY+RIBA (1:1 combination) showed an EC50 of 4.52±1.42 μM. When compared, DOXY showed higher inhibition of viral infectivity and entry than RIBA. In contrast however, RIBA showed higher inhibition against viral replication in target cells compared to DOXY. Assays using mice as animal models revealed that DOXY+RIBA effectively inhibited CHIKV replication and attenuated its infectivity in vivo. Further experimental and clinical studies are warranted to investigate their potential application for clinical intervention of CHIKV disease.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  5. Muhamad M, Kee LY, Rahman NA, Yusof R
    Int J Biol Sci, 2010 May 23;6(3):294-302.
    PMID: 20567498
    Dengue viruses, mosquito-borne members of the Flaviviridae family, are the causative agents of dengue fever and its associated complications, dengue haemorrhagic fever and dengue shock syndrome. To date, more than 2.5 billion people in over 100 countries are at risk of infection, and approximately 20 million infections were reported annually. There is currently no treatment or vaccine available for dengue infection. This study employed a whole-cell organism model or in vitro methods to study the inhibitory property of the flavanoid-derived compounds against DENV2 activity. Results showed that at concentration not exceeding the maximum non-toxic dose (MNTD), these compounds completely prevented DENV2 infection in HepG2 cells as indicated by the absence of cytophatic effects. The in vitro antiviral activity assessed in HepG2 cells employing virus inhibition assay showed high inhibitory activity in a dose dependent manner. At concentration below MNTD, compounds exhibited inhibitory activity against DENV2 with a range of potency strengths of 72% to 100%. The plaque forming unit per ml (pfu/ml) was reduced prominently with a maximum reduction of 98% when the infected HepG2 cells were treated with the highest non-toxic dose of compounds. The highly potent activity of the compounds against DENV2 infection strongly suggests their potential as a lead antiviral agent for dengue.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  6. Lim SG, Aghemo A, Chen PJ, Dan YY, Gane E, Gani R, et al.
    Lancet Gastroenterol Hepatol, 2017 01;2(1):52-62.
    PMID: 28404015 DOI: 10.1016/S2468-1253(16)30080-2
    The Asia-Pacific region has disparate hepatitis C virus (HCV) epidemiology, with prevalence ranging from 0·1% to 4·7%, and a unique genotype distribution. Genotype 1b dominates in east Asia, whereas in south Asia and southeast Asia genotype 3 dominates, and in Indochina (Vietnam, Cambodia, and Laos), genotype 6 is most common. Often, availability of all-oral direct-acting antivirals (DAAs) is delayed because of differing regulatory requirements. Ideally, for genotype 1 infections, sofosbuvir plus ledipasvir, sofosbuvir plus daclatasvir, or ombitasvir, paritaprevir, and ritonavir plus dasabuvir are suitable. Asunaprevir plus daclatasvir is appropriate for compensated genotype 1b HCV if baseline NS5A mutations are absent. For genotype 3 infections, sofosbuvir plus daclatasvir for 24 weeks or sofosbuvir, daclatasvir, and ribavirin for 12 weeks are the optimal oral therapies, particularly for patients with cirrhosis and those who are treatment experienced, whereas sofosbuvir, pegylated interferon, and ribavirin for 12 weeks is an alternative regimen. For genotype 6, sofosbuvir plus pegylated interferon and ribavirin, sofosbuvir plus ledipasvir, or sofosbuvir plus ribavirin for 12 weeks are all suitable. Pegylated interferon plus ribavirin has been replaced by sofosbuvir plus pegylated interferon and ribavirin, and all-oral therapies where available, but cost and affordability remain a major issue because of the absence of universal health coverage. Few patients have been treated because of multiple barriers to accessing care. HCV in the Asia-Pacific region is challenging because of the disparate epidemiology, poor access to all-oral therapy because of availability, cost, or regulatory licensing. Until these problems are addressed, the burden of disease is likely to remain high.
    Matched MeSH terms: Antiviral Agents/therapeutic use*
  7. Yoneda M
    Nippon Rinsho, 2016 12;74(12):1973-1978.
    PMID: 30550652
    Nipah and Hendra virus were first identified in mid 1990s in Australia and Malaysia, caus- ing epidemics with high mortality rate in affected animals and humans. Since their first emer- gence, they continued to re-emerge in Australia and South East Asia almost every year. Nipah and Hendra virus were classified in the new genus Henipavirus because of their un- common features amongst Paramyxoviridae. Henipaviruses are zoonotic paramyxoviruses with a broad tropism, and cause severe acute respiratory disease and encephalitis. Their high virulence and wide host range make them to be given Biosecurity Level 4 status. This review summarizes details of Henipavirus emergence, reservoir hosts and pathology, and introduce recent progress in vaccines and antivirals.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  8. Wong XK, Ng CS, Yeong KY
    Bioorg Chem, 2024 Mar;144:107150.
    PMID: 38309002 DOI: 10.1016/j.bioorg.2024.107150
    Nucleobases serve as essential molecular frameworks present in both natural and synthetic compounds that exhibit notable antiviral activity. Through molecular modifications, novel nucleobase-containing drugs (NCDs) have been developed, exhibiting enhanced antiviral activity against a wide range of viruses, including the recently emerged SARS‑CoV‑2. This article provides a detailed examination of the significant advancements in NCDs from 2015 till current, encompassing various aspects concerning their mechanisms of action, pharmacology and antiviral properties. Additionally, the article discusses antiviral prodrugs relevant to the scope of this review. It fills in the knowledge gap by examining the structure-activity relationship and trend of NCDs as therapeutics against a diverse range of viral diseases, either as approved drugs, clinical candidates or as early-stage development prospects. Moreover, the article highlights on the status of this field of study and addresses the prevailing limitations encountered.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  9. Cheng J, Wang Y, Hou J, Luo D, Xie Q, Ning Q, et al.
    J Clin Virol, 2014 Dec;61(4):509-16.
    PMID: 25200354 DOI: 10.1016/j.jcv.2014.08.008
    In mainland China, peginterferon (PEG-IFN) alfa-2b 1.0μg/kg/wk for 24 weeks is the approved treatment for HBeAg-positive chronic hepatitis B.
    Matched MeSH terms: Antiviral Agents/therapeutic use*
  10. Tan RSL, Hassandarvish P, Chee CF, Chan LW, Wong TW
    Carbohydr Polym, 2022 Aug 15;290:119500.
    PMID: 35550778 DOI: 10.1016/j.carbpol.2022.119500
    The coronavirus pandemic, COVID-19 has a global impact on the lives and livelihoods of people. It is characterized by a widespread infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), where infected patients may develop serious medical complications or even face death. Development of therapeutic is essential to reduce the morbidity and mortality of infected patients. Chitosan is a versatile biomaterial in nanomedicine and exhibits anti-microbial, anti-cancer and immunomodulatory properties. This review highlights the progress in chitosan design and application pertaining to the anti-viral effects of chitosan and chitosan derivatives (hydroxypropyl trimethylammonium, sulfate, carboxymethyl, bromine, sialylglycopolymer, peptide and phosphonium conjugates) as a function of molecular weight, degree of deacetylation, type of substituents and their degree and site of substitution. The physicochemical attributes of these polymeric therapeutics are identified against the possibility of processing them into nanomedicine which can confer a higher level of anti-viral efficacy. The designs of chitosan for the purpose of targeting SARS-CoV-2, as well as the ever-evolving strains of viruses with a broad spectrum anti-viral activity to meet pandemic preparedness at the early stages of outbreak are discussed.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  11. Wallace J, Hamid S, Mohamed R, Wong T
    Lancet Gastroenterol Hepatol, 2023 Sep;8(9):778-780.
    PMID: 37348526 DOI: 10.1016/S2468-1253(23)00161-9
    Matched MeSH terms: Antiviral Agents/therapeutic use
  12. Ong KC, Wong KT
    Brain Pathol, 2015 Sep;25(5):605-13.
    PMID: 26276024 DOI: 10.1111/bpa.12278
    The genus Henipavirus within the family Paramyxoviridae includes the Hendra virus (HeV) and Nipah virus (NiV) which were discovered in the 1990s in Australia and Malaysia, respectively, after emerging to cause severe and often fatal outbreaks in humans and animals. While HeV is confined to Australia, more recent NiV outbreaks have been reported in Bangladesh, India and the Philippines. The clinical manifestations of both henipaviruses in humans appear similar, with a predominance of an acute encephalitic syndrome. Likewise, the pathological features are similar and characterized by disseminated, multi-organ vasculopathy comprising endothelial infection/ulceration, vasculitis, vasculitis-induced thrombosis/occlusion, parenchymal ischemia/microinfarction, and parenchymal cell infection in the central nervous system (CNS), lung, kidney and other major organs. This unique dual pathogenetic mechanism of vasculitis-induced microinfarction and neuronal infection causes severe tissue damage in the CNS. Both viruses can also cause relapsing encephalitis months and years after the acute infection. Many animal models studied to date have largely confirmed the pathology of henipavirus infection, and provided the means to test new therapeutic agents and vaccines. As the bat is the natural host of henipaviruses and has worldwide distribution, spillover events into human populations are expected to occur in the future.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  13. Saleemi MA, Ahmad B, Benchoula K, Vohra MS, Mea HJ, Chong PP, et al.
    Infect Genet Evol, 2020 11;85:104583.
    PMID: 33035643 DOI: 10.1016/j.meegid.2020.104583
    The emergence of a new coronavirus, in around late December 2019 which had first been reported in Wuhan, China has now developed into a massive threat to global public health. The World Health Organization (WHO) has named the disease caused by the virus as COVID-19 and the virus which is the culprit was renamed from the initial novel respiratory 2019 coronavirus to SARS-CoV-2. The person-to-person transmission of this virus is ongoing despite drastic public health mitigation measures such as social distancing and movement restrictions implemented in most countries. Understanding the source of such an infectious pathogen is crucial to develop a means of avoiding transmission and further to develop therapeutic drugs and vaccines. To identify the etiological source of a novel human pathogen is a dynamic process that needs comprehensive and extensive scientific validations, such as observed in the Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and human immunodeficiency virus (HIV) cases. In this context, this review is devoted to understanding the taxonomic characteristics of SARS-CoV-2 and HIV. Herein, we discuss the emergence and molecular mechanisms of both viral infections. Nevertheless, no vaccine or therapeutic drug is yet to be approved for the treatment of SARS-CoV-2, although it is highly likely that new effective medications that target the virus specifically will take years to establish. Therefore, this review reflects the latest repurpose of existing antiviral therapeutic drug choices available to combat SARS-CoV-2.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  14. Eaton BT, Broder CC, Wang LF
    Curr Mol Med, 2005 Dec;5(8):805-16.
    PMID: 16375714
    Within the past decade a number of new zoonotic paramyxoviruses emerged from flying foxes to cause serious disease outbreaks in man and livestock. Hendra virus was the cause of fatal infections of horses and man in Australia in 1994, 1999 and 2004. Nipah virus caused encephalitis in humans both in Malaysia in 1998/99, following silent spread of the virus in the pig population, and in Bangladesh from 2001 to 2004 probably as a result of direct bat to human transmission and spread within the human population. Hendra and Nipah viruses are highly pathogenic in humans with case fatality rates of 40% to 70%. Their genetic constitution, virulence and wide host range make them unique paramyxoviruses and they have been given Biosecurity Level 4 status in a new genus Henipavirus within the family Paramyxoviridae. Recent studies on the virulence, host range and cell tropisms of henipaviruses provide insights into the unique biological properties of these emerging human pathogens and suggest approaches for vaccine development and therapeutic countermeasures.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  15. Menon BS, Wan Maziah WM
    Malays J Pathol, 2001 Jun;23(1):47-8.
    PMID: 16329548
    The aim of this study was to determine the incidence and outcome of herpes zoster hospitalised children with cancer in Kota Baru. It was a retrospective review from January 1994 to December 1998. The diagnosis of herpes zoster was a clinical one. Herpes zoster was diagnosed in 10 of 188 (5%) children with malignancy. The most common malignancy was leukaemia. Nine children were treated with acyclovir. No child developed visceral dissemination and there were no deaths.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  16. Tang LI, Ling AP, Koh RY, Chye SM, Voon KG
    PMID: 22244370 DOI: 10.1186/1472-6882-12-3
    Dengue fever regardless of its serotypes has been the most prevalent arthropod-borne viral diseases among the world population. The development of a dengue vaccine is complicated by the antibody-dependent enhancement effect. Thus, the development of a plant-based antiviral preparation promises a more potential alternative in combating dengue disease.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  17. Shafi G, Desai S, Srinivasan K, Ramesh A, Chaturvedi R, Uttarwar M
    Mol Genet Genomics, 2021 May;296(3):501-511.
    PMID: 33743061 DOI: 10.1007/s00438-021-01774-1
    Coronavirus disease 2019 (COVID-19), a recent viral pandemic that first began in December 2019, in Hunan wildlife market, Wuhan, China. The infection is caused by a coronavirus, SARS-CoV-2 and clinically characterized by common symptoms including fever, dry cough, loss of taste/smell, myalgia and pneumonia in severe cases. With overwhelming spikes in infection and death, its pathogenesis yet remains elusive. Since the infection spread rapidly, its healthcare demands are overwhelming with uncontrollable emergencies. Although laboratory testing and analysis are developing at an enormous pace, the high momentum of severe cases demand more rapid strategies for initial screening and patient stratification. Several molecular biomarkers like C-reactive protein, interleukin-6 (IL6), eosinophils and cytokines, and artificial intelligence (AI) based screening approaches have been developed by various studies to assist this vast medical demand. This review is an attempt to collate the outcomes of such studies, thus highlighting the utility of AI in rapid screening of molecular markers along with chest X-rays and other COVID-19 symptoms to enable faster diagnosis and patient stratification. By doing so, we also found that molecular markers such as C-reactive protein, IL-6 eosinophils, etc. showed significant differences between severe and non-severe cases of COVID-19 patients. CT findings in the lungs also showed different patterns like lung consolidation significantly higher in patients with poor recovery and lung lesions and fibrosis being higher in patients with good recovery. Thus, from these evidences we perceive that an initial rapid screening using integrated AI approach could be a way forward in efficient patient stratification.
    Matched MeSH terms: Antiviral Agents/therapeutic use
  18. Naing C, Poovorawan Y, Tong KS
    BMC Infect Dis, 2018 Nov 14;18(1):564.
    PMID: 30428847 DOI: 10.1186/s12879-018-3506-x
    BACKGROUND: There are randomized trials assessing a variety of antiviral drugs for hepatitis B virus (HBV), but the relative effectiveness of these drugs in the treatment of patients co-infected with human immunodeficiency virus (HIV) remains unclear. The objectives of the current study were to estimate and rank the relative effectiveness of antiviral drugs for treating HBV and HIV co-infected patients.

    METHODS: Randomized trials, assessing the efficacy of antiviral drugs for HBV and HIV co-infected patients were searched in health-related databases. The methodological quality of the included trials was evaluated using the Cochrane risk of bias tool. Main outcome in this meta-analysis study was the success of treatment by antivirals as determined by virologic response. We performed pairwise and network meta-analysis of these trials and assessed the quality of evidence using the GRADE approach.

    RESULTS: Seven randomized trials (329 participants) were included in this network meta-analysis study. A network geometry was formed with six treatment options including four antiviral drugs, adefovir (ADV), emtricitabine (FTC), lamivudine (LMV) and tenofovir disoproxil fumarate (TDF), combination treatment of TDF plus LMV, and placebo. The weighted percentage contributions of each comparison distributed fairly equally in the entire network of evidence. An assumption of consistency required for network meta-analysis was not violated (the global Wald test for inconsistency: Chi2(4) = 3.63, p = 0.46). The results of estimates showed no differences between the treatment regimens in terms of viral response for treating HBV and HIV co-infected patients, which spanned both benefit and harm (e.g. LMV vs TDF plus LMV: OR: 0.37, 95%CI: 0.06-2.41). Overall, the certainty of evidence was very low in all comparisons (e.g. LMV vs TDF plus LMV: 218 fewer per 1000,121 more to 602 fewer, very low certainty). Therefore, we remained uncertain to the true ranking of the antiviral treatments in HBV/ HIV co-infected patients.

    CONCLUSIONS: The findings suggest that the evidence is insufficient to provide guidance to the relative effectiveness of currently available antiviral drugs with dual activity in treating co-infection of HBV/HIV. Well-designed, large clinical trials in this field to address other important outcomes from different epidemiological settings are recommended.

    Matched MeSH terms: Antiviral Agents/therapeutic use*
  19. Tan DS
    Med J Malaya, 1965 Sep;20(1):19-28.
    PMID: 4221407
    Matched MeSH terms: Antiviral Agents/therapeutic use*
  20. Aljabali AAA, Bakshi HA, Satija S, Metha M, Prasher P, Ennab RM, et al.
    Pharm Nanotechnol, 2020;8(4):323-353.
    PMID: 32811406 DOI: 10.2174/2211738508999200817163335
    BACKGROUND: The newly emerged coronavirus SARS-CoV-2, first reported in December 2019, has infected about five and a half million people globally and resulted in nearly 9063264 deaths until the 24th of June 2020. Nevertheless, the highly contagious virus has instigated an unimaginably rapid response from scientific and medical communities.

    OBJECTIVES: Pioneering research on molecular mechanisms underlying the viral transmission, molecular pathogenicity, and potential treatments will be highlighted in this review. The development of antiviral drugs specific to SARS-CoV-2 is a complicated and tedious process. To accelerate scientific discoveries and advancement, researchers are consolidating available data from associated coronaviruses into a single pipeline, which can be readily made available to vaccine developers.

    METHODS: In order to find studies evaluating the COVID-19 virus epidemiology, repurposed drugs and potential vaccines, web searches and bibliographical bases have been used with keywords that matches the content of this review.

    RESULTS: The published results of SARS-CoV-2 structures and interactomics have been used to identify potential therapeutic candidates. We illustrate recent publications on SARS-CoV-2, concerning its molecular, epidemiological, and clinical characteristics, and focus on innovative diagnostics technologies in the production pipeline. This objective of this review is to enhance the comprehension of the unique characteristics of SARS-CoV-2 and strengthen future control measures.

    Lay Summary: An innovative analysis is evaluating the nature of the COVID-19 pandemic. The aim is to increase knowledge of possible viral detection methods, which highlights several new technology limitations and advantages. We have assessed some drugs currently for patients (Lopinavir, Ritonavir, Anakinra and Interferon beta 1a), as the feasibility of COVID-19 specific antivirals is not presently known. The study explores the race toward vaccine development and highlights some significant trials and candidates in various clinical phases. This research addresses critical knowledge gaps by identifying repurposed drugs currently under clinical trials. Findings will be fed back rapidly to the researchers interested in COVID 19 and support the evidence and potential of possible therapeutics and small molecules with their mode of action.

    Matched MeSH terms: Antiviral Agents/therapeutic use*
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