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Antinociceptive, anti-inflammatory and antipyretic effects of Solanum nigrum chloroform extract in animal models

Zakaria ZA, Gopalan HK, Zainal H, Mohd Pojan NH, Morsid NA, Aris A, et al.

Yakugaku Zasshi, 2006 Nov;126(11):1171-8.
PMID: 17077618

AIM: The present study was carried out to evaluate the antinociceptive, anti-inflammatory and antipyretic effects of chloroform extract of Solanum nigrum leaves using various animal models.
METHODS: The extract was prepared by soaking (1:20; w/v) the air-dried powdered leaves (20 g) in chloroform for 72 hrs followed by evaporation (40 degrees C) under reduced pressure to dryness (1.26 g) and then dissolved (1:50; w/v) in dimethylsulfoxide (DMSO). The supernatant, considered as the stock solution with dose of 200 mg/kg, was diluted using DMSO to 20 and 100 mg/kg, and all doses were administered (s.c.; 10 ml/kg) in mice/rats 30 min prior to tests.
RESULTS: The extract exhibited significant (p<0.05) antinociceptive activity when assessed using the abdominal constriction, hot plate and formalin tests. The extract also produced significant (p<0.05) anti-inflammatory and antipyretic activities when assessed using the carrageenan-induced paw edema and brewer's yeast-induced pyrexia tests. Overall, the activities occurred in a dose-independent manner.
CONCLUSION: The present study demonstrated that the lipid-soluble extract of S. nigrum leaves possessed antinociceptive, anti-inflammatory and anti-pyretic properties and confirmed the traditional claims.

Matched MeSH terms: Fever/drug therapy*
Fulltext Antibiotic prescribing for childhood febrile illness by primary care doctors in Malaysia

Teng CL, Hanafi NS, Ng CJ, Chia YC, Atiya AS

J Paediatr Child Health, 2006 Oct;42(10):612-7.
PMID: 16972968 DOI: 10.1111/j.1440-1754.2006.00937.x

AIM: Fever in children, a mostly benign and self-limiting illness, is often viewed with consternation by the care givers. It results in early consultation and excessive use of antipyretics and antibiotics. In this study, we document the prescribing practice of doctors from three primary care settings in Malaysia and identify the predictors of antibiotic prescription.
METHODS: Interview of care givers bringing febrile children (age = 12 years) to three primary care settings: public primary care clinics, private general practice clinics and a university-based primary care clinic.
RESULTS: Data from 649 children were analysed. Mean age of children 4.1 years and 55% were boys. One-third of the children had prior consultation for the same episode of fever. About 80% of the febrile children were diagnosed to have upper respiratory tract infection, viral fever and gastroenteritis. Overall antibiotic prescribing rate was 36.6% (public primary care clinic 26.8%, private general practice clinic 70.0% and university-based primary care clinic 32.2%). Independent predictors of antibiotic prescription were: clinic setting, longer duration of fever (>7 days), higher temperature (>38 degrees C) and the diagnosis of upper respiratory tract infections. After controlling for demographic and clinical factors, antibiotic prescription in private general practice clinic was seven times higher than public primary care clinic (odds ratio 7.1, 95% confidence interval 4.0-12.7), and 1.6 times higher than university-based primary care clinic (odds ratio 1.6, 95% confidence interval 1.0-2.5).
CONCLUSION: Differences in the patients' demographic and clinical characteristics could not adequately explain the high antibiotic prescribing rate in private general practice clinics. This inappropriately high antibiotic prescribing for febrile children in private general practice clinics is a suitable target for future intervention.

Matched MeSH terms: Fever/drug therapy*
Fulltext A combination of doxycycline and ribavirin alleviated chikungunya infection

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: Chikungunya Fever/drug therapy*
Surveillance study of bacteraemic episodes in febrile neutropenic children

Ariffin H, Navaratnam P, Lin HP

Int J Clin Pract, 2002 May;56(4):237-40.
PMID: 12074201

We prospectively studied the type, frequency and outcome of infections in 513 patients with 762 consecutive episodes of febrile neutropenia (FN) over a five-year period between 1995 and 1999 in a single paediatric oncology unit. The findings were then compared with a similar study carried out in our unit between 1990 and 1994. The types of bacterial isolates and sensitivity patterns were also studied to identify trends and to gauge the suitability of antibiotics chosen for empirical therapy. Bacteraemia was documented in 35.4% of FN episodes, although 70% of patients did not have an obvious site of sepsis. The majority of isolates (61.9%) were gram-negative bacteria, a consistent finding throughout the study period. Resistance to ceftazidime, amikacin and imipenem among gram-negative bacteria was 26.3%, 21.2% and 0.7%, respectively. Methicillin resistance among gram-positive bacteria was 26.3%, while no vancomycin-resistant bacteria were encountered. There were 36 sepsis-related deaths. Factors associated with a fatal outome were prolonged capillary refill time, hypotension, fever above 39 degrees C and pneumonia. Rapid neutrophil recovery was associated with a good prognosis. A change to our current choice of empirical antibiotics for FN, comprising ceftazidime/ceftriaxone and amikacin appears necessary because of the relatively high resistance rates found.

Matched MeSH terms: Fever/drug therapy
Complications of bacteriologically confirmed typhoid fever in children

Malik AS

J Trop Pediatr, 2002 Apr;48(2):102-8.
PMID: 12022423

To find the incidence, markers and nature of complications of typhoid fever, we studied 102 children with cultures positive for Salmonella typhi in a cross-sectional study, prospectively, over a period of almost 5 years. All isolates were sensitive to commonly used antibiotics. One third of these children developed complications which included: anicteric hepatitis, bone marrow suppression, paralytic ileus, myocarditis, psychosis, cholecystitis, osteomyelitis, peritonitis, pneumonia, haemolysis, and syndrome of inappropriate release of antidiuretic hormone (SIADH). Twelve children developed multiple complications. If hepatitis is excluded from the complications, the rate of complications in bacteriologically confirmed cases of typhoid fever drops to 11 per cent. These complications were not related to: the age or sex of patients, duration of illness before admission, use of antibiotics before admission, nutritional status, level of 'O' or 'H' titre, presence of IgM or IgG antibodies, or treatment with chloramphenicol or ampicillin. Children with splenomegaly, thrombocytopenia or leukopenia were more likely to develop complications.

Matched MeSH terms: Typhoid Fever/drug therapy
Chloramphenicol in children: dose, plasma levels and clinical effects

Ismail R, Teh LK, Choo EK

Ann Trop Paediatr, 1998 Jun;18(2):123-8.
PMID: 9924573

Despite concerns about adverse effects, chloramphenicol (CMC) continues to be used in certain situations and, due to its low therapeutic index and variable pharmacokinetics, therapeutic drug monitoring (TDM) is often recommended. At our centre, CMC finds applications in typhoid and meningitis and TDM is routinely performed. Elsewhere in Malaysia, however, CMC is used without TDM. We therefore decided to evaluate our TDM for CMC in relation to its roles in CMC therapy in children, who constitute most of our patients. Our objective was also to develop strategies to improve our TDM for CMC use. Data were collected from 168 children given CMC for various indications and monitored by the TDM service. Plasma CMC was determined by HPLC and used to adjust doses to maintain concentrations within a range of 10-25 micrograms/ml. Outcomes measured included daily temperatures and haematological indices. Daily doses and plasma CMC varied greatly. Doses averaged 40.5 mg/kg for neonates and 75.5 for older children. Average peak concentrations were therapeutic in 60% and trough in 42%. Average duration of fever was 6.3 days and it was unaffected by plasma CMC. Typhoid was eradicated in 97% but nine children with other diagnoses died. Side-effects were confined to mild reversible haematological abnormalities which developed in 11% of children at plasma concentrations which tended to be high. We conclude that CMC remains useful in children with typhoid. Its use for other indications, however, should be reviewed. Routine TDM for CMC is probably not warranted, at least until a clearer role is defined by well designed prospective studies.

Matched MeSH terms: Typhoid Fever/drug therapy*
Fulltext Melioidosis: misdiagnosed in Nepal

Shrestha N, Adhikari M, Pant V, Baral S, Shrestha A, Basnyat B, et al.

BMC Infect Dis, 2019 Feb 19;19(1):176.
PMID: 30782129 DOI: 10.1186/s12879-019-3793-x

BACKGROUND: Melioidosis is a life-threatening infectious disease that is caused by gram negative bacteria Burkholderia pseudomallei. This bacteria occurs as an environmental saprophyte typically in endemic regions of south-east Asia and northern Australia. Therefore, patients with melioidosis are at high risk of being misdiagnosed and/or under-diagnosed in South Asia.
CASE PRESENTATION: Here, we report two cases of melioidosis from Nepal. Both of them were diabetic male who presented themselves with fever, multiple abscesses and developed sepsis. They were treated with multiple antimicrobial agents including antitubercular drugs before being correctly diagnosed as melioidosis. Consistent with this, both patients were farmer by occupation and also reported travelling to Malaysia in the past. The diagnosis was made consequent to the isolation of B. pseudomallei from pus samples. Accordingly, they were managed with intravenous meropenem followed by oral doxycycline and cotrimoxazole.
CONCLUSION: The case reports raise serious concern over the existing unawareness of melioidosis in Nepal. Both of the cases were left undiagnosed for a long time. Therefore, clinicians need to keep a high index of suspicion while encountering similar cases. Especially diabetic-farmers who present with fever and sepsis and do not respond to antibiotics easily may turn out to be yet another case of melioidosis. Ascertaining the travel history and occupational history is of utmost significance. In addition, the microbiologist should be trained to correctly identify B. pseudomallei as it is often confused for other Burkholderia species. The organism responds only to specific antibiotics; therefore, correct and timely diagnosis becomes crucial for better outcomes.

Matched MeSH terms: Fever/drug therapy
Deciphering the potential of baicalin as an antiviral agent for Chikungunya virus infection

Oo A, Rausalu K, Merits A, Higgs S, Vanlandingham D, Bakar SA, et al.

Antiviral Res, 2018 02;150:101-111.
PMID: 29269135 DOI: 10.1016/j.antiviral.2017.12.012

The past decade has seen the re-emergence of Chikungunya virus (CHIKV) as a major global health threat, affecting millions around the world. Although fatal infections are rare among infected patients, the occurrence of long-lasting polyarthralgia has a significant impact on patients' quality of lives and ability to work. These issues were the stimuli for this study to determine the potential of baicalin, a bioflavonoid, as the novel antiviral compound against CHIKV. It was found that baicalin was well tolerated by Vero, BHK-21 and HEK 293T cells with maximal nontoxic doses >600 μM, ≈ 350 μM and ≈110 μM, respectively. Antiviral assays indicated that baicalin was the most effective inhibitor when tested for its direct virucidal activity with EC50 ≈ 7 μM, followed by inhibition of virus entry into the host cell, attachment of virus particle to cellular receptors and finally intracellular replication of viral RNA genome. In silico analysis using molecular docking demonstrated close interactions between baicalin and CHIKV envelope protein with considerably strong binding affinity of -9.7 kcal/mol. qRT-PCR analysis revealed that baicalin had the greatest effect on the synthesis of viral negative stand RNA with EC50 ≈ 0.4 μM followed by the inhibition of synthesis of positive-strand genomic (EC50 ≈ 13 μM) and subgenomic RNAs (EC50 ≈ 14 μM). These readings indicate that the compound efficiently inhibits replicase complexes formation but is a less potent inhibitor of existing replicase complexes. Coherent with this hypothesis, the use of recombinant CHIKV replicons harboring Renilla luciferase marker showed that replication of corresponding replicon RNAs was only slightly downregulated at higher doses of baicalin, with EC50 > 100 μM. Immunofluorescence and western blotting experiments demonstrated dose-dependent inhibition of expression of different viral proteins. It was also observed that levels of important protein markers for cellular autophagy (LC3) and apoptosis (Bax) were reduced in baicalin treatment groups as compared with untreated virus infected controls. In summary, given its low toxicity and high efficacy against CHIKV, baicalin has great potential to be developed as the novel antiviral compound for CHIKV. In vivo studies to evaluate its activity in a more complexed system represent a necessary step for future analysis.

Matched MeSH terms: Chikungunya Fever/drug therapy
Fulltext Delineation of B-cell Epitopes of Salmonella enterica serovar Typhi Hemolysin E: Potential antibody therapeutic target

Chin CF, Lai JY, Choong YS, Anthony AA, Ismail A, Lim TS

Sci Rep, 2017 05 19;7(1):2176.
PMID: 28526816 DOI: 10.1038/s41598-017-01987-8

Hemolysin E (HlyE) is an immunogenic novel pore-forming toxin involved in the pathogenesis of typhoid fever. Thus, mapping of B-cell epitopes of Salmonella enterica serovar Typhi (S. Typhi) is critical to identify key immunogenic regions of HlyE. A random 20-mer peptide library was used for biopanning with enriched anti-HlyE polyclonal antibodies from typhoid patient sera. Bioinformatic tools were used to refine, analyze and map the enriched peptide sequences against the protein to identify the epitopes. The analysis identified both linear and conformational epitopes on the HlyE protein. The predicted linear GAAAGIVAG and conformational epitope PYSQESVLSADSQNQK were further validated against the pooled sera. The identified epitopes were then used to isolate epitope specific monoclonal antibodies by antibody phage display. Monoclonal scFv antibodies were enriched for both linear and conformational epitopes. Molecular docking was performed to elucidate the antigen-antibody interaction of the monoclonal antibodies against the epitopes on the HlyE monomer and oligomer structure. An in-depth view of the mechanistic and positional characteristics of the antibodies and epitope for HlyE was successfully accomplished by a combination of phage display and bioinformatic analysis. The predicted function and structure of the antibodies highlights the possibility of utilizing the antibodies as neutralizing agents for typhoid fever.

Matched MeSH terms: Typhoid Fever/drug therapy
Continuous infusion vs. bolus dosing: implications for beta-lactam antibiotics

Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA

Minerva Anestesiol, 2012 Jan;78(1):94-104.
PMID: 21730935

Beta-lactam antibiotics display time-dependant pharmacodynamics whereby constant antibiotic concentrations rather than high peak concentrations are most likely to result in effective treatment of infections caused by susceptible bacteria. Continuous administration has been suggested as an alternative strategy, to conventional intermittent dosing, to optimise beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) properties. With the availability of emerging data, we elected to systematically investigate the published literature describing the comparative PK/PD and clinical outcomes of beta-lactam antibiotics administered by continuous or intermittent infusion. We found that the studies have been performed in various patient populations including critically ill, cancer and cystic fibrosis patients. Available in vitro PK/PD data conclusively support the administration of beta-lactams via continuous infusion for maximizing bacterial killing from consistent attainment of pharmacodynamic end-points. In addition, clinical outcome data supports equivalence, even with the use of a lower dose by continuous infusion. However, the present clinical data is limited with small sample sizes common with insufficient power to detect advantages in favour of either dosing strategy. With abundant positive pre-clinical data as well as document in vivo PK/PD advantages, large multi-centre trials are needed to describe whether continuous administration of beta-lactams is truly more effective than intermittent dosing.

Matched MeSH terms: Fever/drug therapy
Antinociceptive, anti-inflammatory, and antipyretic properties of an aqueous extract of Dicranopteris linearis leaves in experimental animal models

Zakaria ZA, Ghani ZD, Nor RN, Gopalan HK, Sulaiman MR, Jais AM, et al.

J Nat Med, 2008 Apr;62(2):179-87.
PMID: 18404320 DOI: 10.1007/s11418-007-0224-x

This study was performed out to establish the antinociceptive, anti-inflammatory, and antipyretic properties of an aqueous extract of Dicranopteris linearis leaves in experimental animals. The antinociceptive activity was measured using the abdominal constriction, hot plate, and formalin tests. The anti-inflammatory and antipyretic activities were measured using the carrageenan-induced paw edema and brewer's yeast-induced pyrexia tests, respectively. The extract, obtained after 72 h soaking of the air-dried leaves in distilled water and then prepared in the doses of 13.2, 66.0, 132.0, and 660.0 mg/kg, was administered subcutaneously 30 min before subjecting the animals to the assays mentioned above. Generally, the extract, at all doses used, was found to have significant (P < 0.05) concentration-independent antinociceptive, anti-inflammatory, and anti-pyretic activity. In conclusion, the aqueous extract of D. linearis has antinociceptive, anti-inflammatory, and antipyretic activity, supporting previous claims of its traditional use by the Malays to treat various ailments, particularly fever.

Matched MeSH terms: Fever/drug therapy
Evaluation of the antihyperlipidemic, anti-inflammatory, analgesic, and antipyretic activities of ethanolic extract of Ammi majus seeds in albino rats and mice

Koriem KM, Asaad GF, Megahed HA, Zahran H, Arbid MS

Int J Toxicol, 2012 Jun;31(3):294-300.
PMID: 22550046 DOI: 10.1177/1091581812440889

Pharmacological and biochemical studies on the Ammi majus seeds L. (family Umbelliferae) grown in Egypt are limited. Furocoumarins are the major constituents in the plant seeds. In the present study, the evaluation of the antihyperlipidemic, anti-inflammatory, analgesic, and antipyretic activities on albino rats and mice was done. After 2 months of administration, both the doses (50 and 100 mg/kg body weight [bwt], respectively) of the alcoholic extract of the A. majus seed result in a significant decrease in the concentrations of cholesterol, triglycerides, and low-density lipoprotein and increase in the concentration of high-density lipoprotein. The extract was found to inhibit the rat paw edema at both the doses, which means that it exerts a significant anti-inflammatory activity compared with control-untreated groups at the intervals of 30 and 60 minutes posttreatment. The antipyretic effect of the extract was quite obvious; it showed that 100 mg/kg bwt was more potent in lowering body temperature starting after 1 hour of treatment than the lower dose (50 mg/kg bwt). It is worth to mention that the A. majus extract with its coumarin contents as well as the tested biological activities of the plant was investigated for the first time in the current study. In conclusion, ethanolic extract of the A. majus seeds had antihyperlipidemic, anti-inflammatory, analgesic, and antipyretic activities that are dose dependant.

Matched MeSH terms: Fever/drug therapy
Fulltext The burden of typhoid fever in Klang Valley, Malaysia, 2011-2015

Muhammad EN, Abdul Mutalip MH, Hasim MH, Paiwai F, Pan S, Mahmud MAF, et al.

BMC Infect Dis, 2020 Nov 16;20(1):843.
PMID: 33198646 DOI: 10.1186/s12879-020-05500-x

BACKGROUND: Typhoid fever causes global morbidity and mortality and is a significant health burden, particularly in low- and middle-income countries. The direct fecal-oral route is the main transmission mode, but indirect environmental transmission could occur, particularly in urban settings. This study aimed to investigate the burden and trend of typhoid fever, reporting the coverage system between government and private practice and pattern of multidrug-resistant (MDR) typhoid cases in the urban Klang Valley area from 2011 to 2015.
METHODS: The data from a cross-sectional study retrieved from the e-Notifikasi System, a national reporting system for communicable diseases provided by the Disease Control Division, Ministry of Health Malaysia and secondary data of all the typhoid cases were obtained from the public and private hospitals and laboratories in Klang Valley. Descriptive analysis was performed to examine the sociodemographic characteristics, spatial mapping was conducted to examine trends, and the crude incidence rates of confirmed typhoid cases and percentage of reporting coverage were calculated. Significant differences between MDR and non-MDR Salmonella typhi were determined in the patient's sociodemographic characteristics, which were analyzed using χ2 test. P values fever cases were reported in Klang Valley; however, only 265 cases were confirmed by culture tests. The crude incidence rates of confirmed cases were between 0.5 to 0.7 but peaked at 1.42 per 100,000 population in 2015. Most typhoid fever cases were observed among men (55.6%), individuals aged 21 to 30 years (27.6%), Malaysians (86.3%) and individuals of Malay ethnicity (52.1%). The reporting coverage of confirmed cases was 78.9% and non-reporting coverage of unconfirmed typhoid cases was 79.5%. The predictive value positive (PVP) was 89.3, and 7.5% were detected as MDR Salmonella typhi. Statistical significance was found in gender, citizenship and ethnicity regarding MDR Salmonella typhi (p = 0.004, p = 0.008 and p = 0.034, respectively).
CONCLUSIONS: The local transmission of typhoid is still prevalent in the Klang Valley despite rapid urbanization and development in recent years. These findings are essential for policy makers to plan and implement focused and effective preventative activities to curb typhoid infection in urban areas.

Matched MeSH terms: Typhoid Fever/drug therapy
Inhibitory effects of a peptide-fusion protein (Latarcin-PAP1-Thanatin) against chikungunya virus

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: Chikungunya Fever/drug therapy

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