Displaying publications 1 - 20 of 63 in total

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  1. Navaratnam V, Mansor SM, Mordi MN, Akbar A, Abdullah MN
    Eur J Clin Pharmacol, 1998 Jul;54(5):411-4.
    PMID: 9754985
    OBJECTIVE: A single cross-over, comparative pharmacokinetic study of oral and rectal formulations of 200 mg artesunic acid in 12 healthy Malaysian volunteers is reported.

    METHODS: Plasma concentrations of artesunic acid and dihydroartemisinin were determined simultaneously by HPLC with electrochemical detection. The test drug was well tolerated and no undesirable adverse effects were observed.

    RESULTS: Comparison of pharmacokinetic parameters of artesunic acid after oral and rectal administration showed statistically significant differences in t(max) and AUC, with no changes for Cmax and t1/2. As for dihydroartemisinin, differences were observed for t(max) and Cmax but not for AUC.

    CONCLUSION: There appear to be pharmacokinetic differences between oral and rectal modes of administration. The significance of these findings should be explored in malaria patients before appropriate therapeutic regimens are devised.

  2. Mak JW, Navaratnam V, Grewel JS, Mansor SM, Ambu S
    Am J Trop Med Hyg, 1993 Apr;48(4):591-6.
    PMID: 8480868
    A clinical trial on the efficacy of a single oral dose of ivermectin at 20, 50, 100, and 200 micrograms/kg was carried out in 40 subjects with subperiodic Brugia malayi microfilaremia. There was no significant difference in the clearance of microfilaremia in the four treatment groups, and the lowest geometric mean microfilarial count (GMC) achieved in the 40 subjects was 8.8/ml or 8.3% of the initial count (106.1/ml), at two weeks post-treatment. The GMC started to increase at one month post-treatment and by six months was 22.2% of the initial GMC. Only 27.5%, 23.1%, 15.0%, and 18.9% of subjects were amicrofilaremic at two, four, 12, and 24 weeks post-treatment, respectively. Mild fever in 35% of the subjects was the primary side reaction and was more common in those with microfilarial counts > or = 500/ml (85.7%) than in those with counts < 500/ml (32%). The clearance of B. malayi microfilaremia by ivermectin was less rapid than that reported for Wuchereria bancrofti. The smaller number of side reactions encountered in the present study compared with those reported for bancroftian filariasis is probably related to the lower microfilarial density in the present subjects. Since ivermectin at a single oral dose of 20-200 micrograms/kg can reduce the GMC to less than 10% at two weeks and maintain it below 25% of the initial level even at six months post-treatment, it is recommended that the drug be seriously evaluated for use in the control of brugian filariasis.
  3. Parapini S, Olliaro P, Navaratnam V, Taramelli D, Basilico N
    Antimicrob Agents Chemother, 2015 Jul;59(7):4046-52.
    PMID: 25918150 DOI: 10.1128/AAC.00183-15
    Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.
  4. Navaratnam V, Forrester DL, Eg KP, Chang AB
    Respirology, 2019 02;24(2):115-126.
    PMID: 30500093 DOI: 10.1111/resp.13451
    Bronchiectasis is a chronic lung disease associated with structurally abnormal bronchi, clinically manifested by a persistent wet/productive cough, airway infections and recurrent exacerbations. Early identification and treatment of acute exacerbations is an integral part of monitoring and annual review, in both adults and children, to minimize further damage due to infection and inflammation. Common modalities used to monitor disease progression include clinical signs and symptoms, frequency of exacerbations and/or number of hospital admissions, lung function (forced expiratory volume in 1 s (FEV1 )% predicted), imaging (radiological severity of disease) and sputum microbiology (chronic infection with Pseudomonas aeruginosa). There is good evidence that these monitoring tools can be used to accurately assess severity of disease and predict prognosis in terms of mortality and future hospitalization. Other tools that are currently used in research settings such as health-related quality of life (QoL) questionnaires, magnetic resonance imaging and lung clearance index can be burdensome and require additional expertise or resource, which limits their use in clinical practice. Studies have demonstrated that cross-infection, especially with P. aeruginosa between patients with bronchiectasis is possible but infrequent. This should not limit participation of patients in group activities such as pulmonary rehabilitation, and simple infection control measures should be carried out to limit the risk of cross-transmission. A multidisciplinary approach to care which includes respiratory physicians, chest physiotherapists, nurse specialists and other allied health professionals are vital in providing holistic care. Patient education and personalized self-management plans are also important despite limited evidence it improves QoL or frequency of exacerbations.
  5. Mansor SM, Navaratnam V, Yahaya N, Nair NK, Wernsdorfer WH, Degen PH
    J Chromatogr B Biomed Appl, 1996 Jul 12;682(2):321-5.
    PMID: 8844426
    A rapid and selective high-performance liquid chromatographic assay for determination of a new antimalarial drug (benflumetol, BFL) is described. After extraction with hexane-diethyl ether (70:30, v/v) from plasma, BFL was analysed using a C18 Partisil 10 ODS-3 reversed-phase stainless steel column and a mobile phase of acetonitrile-0.1 M ammonium acetate (90:10, v/v) adjusted to pH 4.9 with ultraviolet detection at 335 nm. The mean recovery of BFL over a concentration range of 50-400 ng/ml was 96.8 +/- 5.2%. The within-day and day-to-day coefficients of variation were 1.8-4.0 and 1.8-4.2%, respectively. The minimum detectable concentration in plasma for BFL was 5 ng/ml with a C.V. of less than 10%. This method was found to be suitable for clinical pharmacokinetic studies.
  6. Damodaran T, Hassan Z, Navaratnam V, Muzaimi M, Ng G, Müller CP, et al.
    Behav Brain Res, 2014 Dec 15;275:252-8.
    PMID: 25239606 DOI: 10.1016/j.bbr.2014.09.014
    Cerebral ischemia is one of the leading causes of death and long-term disability in aging populations, due to the frequent occurrence of irreversible brain damage and subsequent loss of neuronal function which lead to cognitive impairment and some motor dysfunction. In the present study, the real time course of motor and cognitive functions were evaluated following the chronic cerebral ischemia induced by permanent, bilateral occlusion of the common carotid arteries (PBOCCA). Male Sprague Dawley rats (200-300g) were subjected to PBOCCA or sham-operated surgery and tested 1, 2, 3 and 4 weeks following the ischemic insult. The results showed that PBOCCA significantly reduced step-through latency in a passive avoidance task at all time points when compared to the sham-operated group. PBOCCA rats also showed significant increase in escape latencies during training in the Morris water maze, as well as a reduction of the percentage of times spend in target quadrant of the maze at all time points following the occlusion. Importantly, there were no significant changes in locomotor activity between PBOCCA and sham-operated groups. The BDNF expression in the hippocampus was 29.3±3.1% and 40.1±2.6% on day 14 and 28 post PBOCCA, respectively compared to sham-operated group. Present data suggest that the PBOCCA procedure effectively induces behavioral, cognitive symptoms associated with cerebral ischemia and, consequently, provides a valuable model to study ischemia and related neurodegenerative disorder such as Alzheimer's disease and vascular dementia.
  7. Navaratnam V, Foong K
    Med J Malaysia, 1989 Jun;44(2):92-103.
    PMID: 2626130
    Information from the national drug abuse monitoring system was analysed to determine the trends in extent and pattern of drug dependence in Malaysia over the period 1970 to 1986. The annual incidence and prevalence rates of reported drug dependents increased by many folds when compared to the early seventies. Generally, the profile of drug dependents identified has remained relatively stable throughout the years. A stable pattern of drug abuse was also noted over this period. Factors influencing the trend patterns are discussed, as well as the implications of these findings for policy purposes.
  8. Navaratnam V, Foong K
    Curr Med Res Opin, 1989;11(9):600-9.
    PMID: 2612204
    The temporal sequence of drug use should reveal which drugs are precursors to heroin and which drugs are used subsequent to the establishment of heroin addiction as adjunctive drugs. This temporal sequence was examined in an epidemiological study. Out of 249 opiate addicts interviewed in the area of Penang, Malaysia, this sequence of drugs could be obtained in 248 cases. The mean (median) age for first use of nicotine is 15.5 (15) years, alcohol 18.4 (18) years, cannabis 17.8 (17) years, heroin 21.8 (21) years, opium 22.8 (22) years, and benzodiazepines 25.8 (25) years. The age of first use of different drug types is presented in some detail. The patterns of sequence of drug use was analyzed for the five major and most frequently reported drugs, i.e. alcohol, cannabis, heroin, opium and benzodiazepines. Nicotine, used as first drug in almost all cases, was omitted in this analysis. A clear trend to multiple drug abuse emerges from this analysis; the biggest number of cases were users of 4 drugs (81 cases), followed by 3 drugs (59 cases) and 5 drugs (58 cases). Thus, nicotine, alcohol and cannabis are precursors of heroin addiction. Other adjunctive drugs become important only after heroin addiction. Among these substances, opium and benzodiazepines are numerically preponderant.
  9. Navaratnam V, Foong K
    Bull Narc, 1989;41(1-2):53-65.
    PMID: 2765720
    Monitoring systems are useful epidemiological instruments for assessing the problem of drug abuse. The rapid growth of the drug dependence problem in Malaysia led to increased awareness of the need for a system for continuous monitoring of the situation. Preliminary work on the design of an appropriate monitoring system was initiated in 1976. A fully integrated national reporting system was established in 1978, linking all public services and agencies coming into contact with drug-dependent persons, including law enforcement agencies, drug abuse treatment and rehabilitation centres, and social and welfare institutions. The information system included a mechanism for systematic gathering, processing, analysing and presenting essential data on the prevention, control and management of drug abuse problems. It also included reporting on drug-related events, such as hospitalizations and arrests, as well as data on known drug-dependent persons and new cases of dependence. The system has been used for routine monitoring of the extent, trends, patterns and other characteristics of drug abuse problems in Malaysia, providing basic information for policy-making and programme planning. On the basis of data generated by the system, it was estimated that the prevalence rate of drug-dependent persons per 100,000 population increased from 84.3 in 1976 to 754.6 in 1986. It was estimated that there were 119,001 drug-dependent persons in Malaysia in 1986.
  10. Navaratnam V, Foong K
    Curr Med Res Opin, 1990;11(10):620-30.
    PMID: 1968829
    In a recent epidemiological study of 249 opiate addicts in the State of Penang, Malaysia, the use of benzodiazepines, its temporal relationship to opiate addiction and the reasons for use of benzodiazepines were examined. Just over a half of the opiate addicts indicated use of benzodiazepines in their lifetime. Use of 7 different benzodiazepines was reported, among them flunitrazepam most frequently. A substantial proportion had discontinued the use of benzodiazepines after initial experimentation. Just over a quarter had used them in the last 24 hours. Benzodiazepine use starts on average 3 to 6 years later than heroin use. The most common reason cited for benzodiazepine use was to enhance the feeling of 'high' from the opiates. These findings can be explained, at least partly, by economic factors. Reasons that could be qualified as attempts to autotherapy did not exceed 20%. None of the opiate addicts had reported isolated benzodiazepine use for fun and pleasure. From the time course of use as well as from the reasons given by the addicts, it is evident that benzodiazepines are not primary drugs of abuse. Comparing their figures from Malaysia with figures from Germany and England the authors cannot explain the preferred use of flunitrazepam by Malaysian addicts by the existence of special properties of this substance.
  11. Navaratnam V, Foong K
    Curr Med Res Opin, 1990;11(10):611-9.
    PMID: 2311417
    In a study of 249 opiate (mainly heroin) addicts special attention was paid to adjunctive drug use. Generally, nicotine (cigarette smoking), alcohol and cannabis preceded the use of heroin, and continued to be used as adjunctive drugs after the establishment of heroin addiction. Nicotine was the most common substance used together with opiates. Alcohol and cannabis were used as adjunctive drugs in about two-thirds of the cases. In the late stages of heroin addiction, benzodiazepines were also used concomitantly with opiates. The most frequently reported reason for the use of adjunctive drugs was to intensify the effect of the opiate. Three-quarters or more of the addicts had used different adjunctive drugs to boost the euphoric feeling derived from the primary drug, i.e. heroin. Attempt at self-treatment of withdrawal symptoms was a less frequently reported reason for adjunctive drug use. The findings show that heroin addiction is the major problem. The use of adjunctive drugs, especially benzodiazepines, can be partly explained on economic grounds. They must be clearly distinguished from the primary drug of abuse, heroin. For policy-making decisions, it is important that the elimination of heroin abuse through effective prevention measures would ultimately wipe out the problem of adjunctive drug use, while reduction of the overall supply of heroin without reduction in actual demand might result in an increasing trend to adjunctive drug use.
  12. Suhaimi FW, Yusoff NH, Hassan R, Mansor SM, Navaratnam V, Müller CP, et al.
    Brain Res Bull, 2016 09;126(Pt 1):29-40.
    PMID: 27018165 DOI: 10.1016/j.brainresbull.2016.03.015
    Kratom or its main alkaloid, mitragynine is derived from the plant Mitragyna speciosa Korth which is indigenous to Southeast Asian countries. This substance has become widely available in other countries like Europe and United States due to its opium- and coca-like effects. In this article, we have reviewed available reports on mitragynine and other M. speciosa extracts. M. speciosa has been proven to have a rewarding effect and is effective in alleviating the morphine and ethanol withdrawal effects. However, studies in human revealed that prolonged consumption of this plant led to dependence and tolerance while cessation caused a series of aversive withdrawal symptoms. Findings also showed that M. speciosa extracts possess antinociceptive, anti-inflammatory, anti-depressant, and muscle relaxant properties. Available evidence further supports the adverse effects of M. speciosa preparations, mitragynine on cognition. Pharmacological activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Physicochemical properties of mitragynine have been documented which may further explain the variation in pharmacological responses. In summary, current researchs on its main indole alkaloid, mitragynine suggest both therapeutic and addictive potential but further research on its molecular effects is needed.
  13. Liew K, Yong PV, Lim YM, Navaratnam V, Ho AS
    Toxicol In Vitro, 2014 Apr;28(3):335-9.
    PMID: 24291160 DOI: 10.1016/j.tiv.2013.11.008
    Metastasis contributes to the escalating mortality rate among cancer patients worldwide. The search for novel and more effective anti-metastatic agent is crucial owing to the lack of anticancer drugs that can successfully combat metastasis. Hence, this study aims to examine the effects of 2-Methoxy-1,4-Naphthoquinone (MNQ) towards the metastasis of MDA-MB-231 cells. In invasion assays, the number of cells permeating across a Matrigel barrier was found to be decreased in a dose-dependent manner upon treatment with MNQ (0-7.5 μM). In wound-healing migration assays, MNQ exhibited dose-dependent inhibition of cell migration in which significant reduction in the zone of closure was observed as compared to untreated controls. Furthermore, the proteolytic activity of a pivotal metastatic mediator, matrix metalloproteinase-9 (MMP-9) was also downregulated by MNQ as determined by gelatin zymography. This study reports for the first time, the ability of MNQ to inhibit the invasion and migration characteristics of a highly metastatic MDA-MB-231 cancer cell line.
  14. Liew K, Yong PV, Navaratnam V, Lim YM, Ho AS
    Phytomedicine, 2015 May 15;22(5):517-27.
    PMID: 25981917 DOI: 10.1016/j.phymed.2015.03.007
    We have previously reported the anti-metastatic effects of 2-methoxy-1,4-naphthoquinone (MNQ) against MDA-MB-231 cell line.
  15. Lokman Hakim S, Sharifah Roohi SW, Zurkurnai Y, Noor Rain A, Mansor SM, Palmer K, et al.
    Trans R Soc Trop Med Hyg, 1996 5 1;90(3):294-7.
    PMID: 8758083
    Uncomplicated falciparum malaria patients were randomly assigned to receive either 25 mg/kg chloroquine (CHL) over 3 d or a statim dose of 25 mg/kg sulfadoxine (SDX) plus 1.25 mg/kg pyrimethamine (PYR). Patients were followed up for 28 d and the parasite response graded according to World Health Organization criteria. Overall resistance to CHL was 63.3% and 47.4% to SDX/PYR. RI, RII and RIII rates were 9.1%, 42.4% and 12.1% for CHL and 10.5%, 21.1% and 15.8% for SDX/PYR, respectively. Degree and rates of resistance to CHL were significantly correlated with pre-treatment parasite density, but not those to SDX/PYR. Plasma CHL and SDX/PYR levels were within the reported ranges and were not significantly different in patients with sensitive and resistant responses.
  16. Navaratnam V, Jamaludin A, Raman N, Mohamed M, Mansor SM
    Drug Alcohol Depend, 1994 Feb;34(3):231-6.
    PMID: 8033761
    Thirty-eight, adult, male, detoxified, Malaysian opiate addicts participated in this double-blind clinical evaluation of naltrexone. Addicts from three ethnic groups: Chinese, Malays, and Indians received a weekly regimen of naltrexone (100 mg on Days 1 and 3, and 150 mg on Day 5). Subjects were randomly assigned to receive intravenous challenge with either 25 mg heroin or placebo 12, 24, 48, and 72 h after the third naltrexone dose. Physiological and subjective parameters were measured at each challenge interval. Results indicated that naltrexone was effective in blocking the physiological and psychological effects of heroin for at least 48 and 72 h, respectively, in detoxified Malaysian opiate addicts. The efficacy of naltrexone did not differ among the three ethnic groups evaluated in this study.
  17. Navaratnam V, Mordi MN, Mansor SM
    J Chromatogr B Biomed Sci Appl, 1997 Apr 25;692(1):157-62.
    PMID: 9187395
    A selective reproducible high-performance liquid chromatographic assay for the simultaneous quantitative determination of the antimalarial compound artesunic acid (ARS), dihydroartemisinin (DQHS) and artemisinin (QHS), as internal standard, is described. After extraction from plasma, ARS and DQHS were analysed using an Econosil C8 column and a mobile phase of acetonitrile-0.05 M acetic acid (42:58, v/v) adjusted to pH 5.0 and electrochemical detection in the reductive mode. The mean recovery of ARS and DQHS over a concentration range of 50-200 ng/ml was 75.5% and 93.5%, respectively. The within-day coefficients of variation were 4.2-7.4% for ARS and 2.6-4.9% for DQHS. The day-to-day coefficients of variation were 1.6-9.6% and 0.5-8.3%, respectively. The minimum detectable concentration for ARS and DQHS in plasma was 4.0 ng/ml for both compounds. The method was found to be suitable for use in clinical pharmacological studies.
  18. Ramanathan S, Karupiah S, Nair NK, Olliaro PL, Navaratnam V, Wernsdorfer WH, et al.
    PMID: 16046285
    A new approach using a simple solid-phase extraction technique has been developed for the determination of pyronaridine (PND), an antimalarial drug, in human plasma. After extraction with C18 solid-phase sorbent, PND was analyzed using a reverse phase chromatographic method with fluorescence detection (at lambda(ex)=267 nm and lambda(em)=443 nm). The mean extraction recovery for PND was 95.2%. The coefficient of variation for intra-assay precision, inter-assay precision and accuracy was less than 10%. The quantification limit with fluorescence detection was 0.010 microg/mL plasma. The method described herein has several advantages over other published methods since it is easy to perform and rapid. It also permits reducing both, solvent use and sample preparation time. The method has been used successfully to assay plasma samples from clinical pharmacokinetic studies.
  19. Yusoff NH, Suhaimi FW, Vadivelu RK, Hassan Z, Rümler A, Rotter A, et al.
    Addict Biol, 2016 Jan;21(1):98-110.
    PMID: 25262913 DOI: 10.1111/adb.12185
    Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.
  20. Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R, et al.
    Neurosci Biobehav Rev, 2013 Feb;37(2):138-51.
    PMID: 23206666 DOI: 10.1016/j.neubiorev.2012.11.012
    Kratom (or Ketum) is a psychoactive plant preparation used in Southeast Asia. It is derived from the plant Mitragyna speciosa Korth. Kratom as well as its main alkaloid, mitragynine, currently spreads around the world. Thus, addiction potential and adverse health consequences are becoming an important issue for health authorities. Here we reviewed the available evidence and identified future research needs. It was found that mitragynine and M. speciosa preparations are systematically consumed with rather well defined instrumentalization goals, e.g. to enhance tolerance for hard work or as a substitute in the self-treatment of opiate addiction. There is also evidence from experimental animal models supporting analgesic, muscle relaxant, anti-inflammatory as well as strong anorectic effects. In humans, regular consumption may escalate, lead to tolerance and may yield aversive withdrawal effects. Mitragynine and its derivatives actions in the central nervous system involve μ-opioid receptors, neuronal Ca²⁺ channels and descending monoaminergic projections. Altogether, available data currently suggest both, a therapeutic as well as an abuse potential.
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