BACKGROUND: Glucuronidation catalyzed by uridine 5'- diphospho-glucuronosyltransferase (UGT) is a major phase II drug metabolism reaction which facilitates drug elimination. Inhibition of UGT activity can cause drug-drug interaction. Therefore, it is important to determine the inhibitory potentials of drugs on glucuronidation.
OBJECTIVE: The objective was to evaluate the inhibitory potentials of mitragynine, 7-hydroxymitragynine, ketamine and buprenorphine, respectively on 4-methylumbelliferone (4-MU) glucuronidation in rat liver microsomes, human liver microsomes and recombinant human UGT1A1 and UGT2B7 isoforms.
MATERIALS AND METHODS: The effects of the above four compounds on the formation of 4-MU glucuronide from 4-MU by rat liver microsomes, human liver microsomes, recombinant human UGT1A1 and UGT2B7 isoforms were determined using high-performance liquid chromatography with ultraviolet detection.
RESULTS: For rat liver microsomes, ketamine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.21 ± 1.51 μM followed by buprenorphine with an IC50 value of 73.22 ± 1.63 μM. For human liver microsomes, buprenorphine strongly inhibited 4-MU glucuronidation with an IC50 value of 6.32 ± 1.39 μM. For human UGT1A1 isoform, 7-hydroxymitragynine strongly inhibited 4-MU glucuronidation with an IC50 value of 7.13 ± 1.16 μM. For human UGT2B7 isoform, buprenorphine strongly inhibited 4-MU glucuronidation followed by 7-hydroxymitragynine and ketamine with respective IC50 values of 5.14 ± 1.30, 26.44 ± 1.31, and 27.28 ± 1.18 μM.
CONCLUSIONS: These data indicate the possibility of drug-drug interaction if 7-hydroxymitragynine, ketamine, and buprenorphine are co-administered with drugs that are UGT2B7 substrates since these three compounds showed significant inhibition on UGT2B7 activity. In addition, if 7-hydroxymitragynine is to be taken with other drugs that are highly metabolized by UGT1A1, there is a possibility of drug-drug interaction to occur.
KEYWORDS: 4-methylumbelliferone; 7-hydroxymitragynine; buprenorphine; glucuronidation; ketamine; mitragynine
In a previous paper the authors reported on the methods and zoogeographical background of a survey of animal leptospirosis in Malaya, giving a broad analysis of results. In the present paper the localities studied in towns and villages, in ricefields, in secondary forest and scrub and in primary forest are compared in detail. In towns and villages infection rates in rats were low, except in a seaport town where the invading R. norvegicus was heavily infected. In ricefields infection is maintained in R. argentiventer, alone or in association with R. exulans. In secondary forest and scrub there is overlap with forest species and the main hosts of leptospires appear to be R. exulans and R. jalorensis. In primary forest giant rats and, to a lesser degree, spiny rats are the main hosts.Ground-living rats appear to be better maintenance hosts than those scrambling on vegetation or arboreal rats. With some exceptions the incidence of infection of a rat species in an area was found to be in direct relation to the proportion that species formed of the total rat population. The critical number of rats for maintenance of leptospirosis in an area is estimated to be about two rats of the maintenance species per hectare.
Mitragyna speciosa Korth is a medicinal plant indigenous to Thailand and Malaysia and has been known for its narcotic and coca-like effects. Many studies have been performed on the antinociceptive effect of the plant extracts of Thai origin; however, limited studies have been reported till date on M. speciosa extracts of Malaysian origin. Various concentrations of alkaloid (5-20 mg/kg), methanolic (50-200 mg/kg), and aqueous (100-400 mg/kg) extracts of Malaysian M. speciosa leaves were prepared and orally administered to nine groups of rats. Morphine (5 mg/kg, s.c.) and aspirin (300 mg/kg, p.o.) were used as control. Antagonism of the antinociceptive activity was evaluated by pretreatment with naloxone at a dose of 2 mg/kg (i.p.). Results showed that oral administration of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts significantly prolonged the latency of nociceptive response compared with control groups in both hot plate and tail flick tests (P < 0.05). Antinociceptive action of the alkaloid (20 mg/kg), methanolic (200 mg/kg), and aqueous (400 mg/kg) extracts was significantly blocked by naloxone. In conclusion, these results suggest the presence of antinociceptive effect in various extracts of Malaysian M. speciosa leaves. In addition, the antinociceptive effective doses vary depending on the type of solvents used for extraction.
Breinlia booliati Singh & Ho, 1973 first described from Peninsular Malaysia has been shown to infect a large range of murids ranging in distribution from southern Thailand, Peninsular Malaysia, Sarawak to Ciloto, Indonesia. Probably further work will reveal a greater host range as well as its geographical distribution. The vectors involved in its transmission need to be elucidated.
Hiperkolesterolemia merupakan suatu keadaan yang dikaitkan dengan perubahan aras lipid serum serta peningkatan aras peroksidaan lipid. Kajian ini dilakukan untuk melihat kesan ekstrak akues isi dan kulit buah Hylocereus polyrhizus (HP) terhadap jumlah kolesterol dan trigliserid (TG) serum serta aras malonaldehid (MDA-TBAR) hati tikus teraruh hiperkolesterolemia. Tikus Sprague dawley jantan diaruh menjadi hiperkolesterolemia dengan pemberian diet rat chow bersama 15% minyak sapi selama 8 minggu dan 0.02 g kolesterol secara suap paksa dua kali seminggu. Tikus-tikus diberi perlakuan ekstrak isi dan kulit buah HP, 300 mg/kg secara suap paksa selama 10 hari. Hasil menunjukkan aras kolesterol menurun secara signifikan (p<0.05) pada kedua-dua kumpulan hiperkolesterolemia yang diberi rawatan ekstrak isi dan kulit buah HP sebanyak 43.53% dan 51.36% berbanding tikus kawalan hiperkolesterolemia. Aras TG menunjukkan penurunan secara signifikan (p<0.05) sebanyak 38.0% bagi kumpulan tikus yang diberi rawatan ekstrak isi dan 42.98% bagi rawatan dengan ekstrak kulit buah HP. Peningkatan aras MDA-TBAR hati telah direncat dengan penurunan aras MDA-TBAR sebanyak 56.85% bagi kumpulan tikus yang diberi ekstrak kulit serta sedikit penurunan iaitu 10.27% bagi tikus yang diberi ekstrak isi berbanding tikus kawalan hiperkolesterolemia. Kajian ini menunjukkan bahawa kedua-dua ekstrak akues isi dan kulit buah HP merendahkan aras lipid serum serta aras MDA-TBAR hati pada tikus teraruh hiperkolesterolemia. Walau bagaimanapun, kesan ekstrak kulit lebih jelas berbanding ekstrak isi yang mungkin disebabkan oleh kandungan betasianin yang lebih tinggi dalam kulit berbanding isi buah HP.
The effects of differences in smoke concentration and exposure duration in Sprague Dawley rats to determine variation in type and severity of the testis apoptosis were evaluated. The daily dosages were 10, 20 and 30 non-filter cigarettes for a period of 2, 4, 6, 8 and 12 weeks. Mainstream smoke exposure suppressed body weight gain in all regimens. A dose-related increase in plasma nicotine concentration was observed in smoke-exposed groups for 4, 6, 8 and 12 week regimens. Histopathological examination of the exposed groups showed disturbances in the stages of spermatogenesis, tubules atrophying and these appeared to be dose-related. Cytoplasmic caspase-3 immunostaining was detected both in Sertoli cells and germ cells in smoke-exposure groups. An increase in TUNEL-positive cells of testicular cells was observed after 6 weeks of cigarette exposure. The results indicate that cigarette exposure concentration and duration have interaction effect to induce apoptosis in the rat testes.
Lignosus rhinocerus (L. rhinocerus), which is known locally as Tiger Milk mushroom, is traditionally used in the treatment of asthma by indigenous communities in Malaysia. However, to date, its efficacy on asthma has not been confirmed by scientific studies and there is also sparse information available on its active constituents. In this study, the volatile constituent of L. rhinocerus hot water extract was investigated using gas chromatography mass spectrometry (GC-MS). The potential effects of L. rhinocerus extract for anti-asthmatic activity was further investigated on ovalbumin (OVA)-sensitized asthmatic Sprague Dawley rats.
BACKGROUND: Mitragyna speciosa (MS) or ketum is primarily found in Southeast Asia, particularly in northern Malaysia and Thailand. The medicinal value of this plant has attracted significant attention from both herbal medicine practitioners and scientists worldwide. Despite having illegal consumption status, the plant merits study. We conducted a series of experiments to test our hypothesis that ketum impairs both learning and memory in rats.
METHODS: Ketum leaves were extracted using methanol and standardised for the amount of its pure compound, mitragynine. Rats were divided into groups for a passive avoidance task and long-term potentiation (LTP) extracellular recording. In the extracellular recording condition, rats were grouped into control, MS100 (100 mg/kg of ketum extract), MS200 (200 mg/kg of ketum extract), and MS500 (500 mg/kg of ketum extract) groups. An additional group that received morphine was included in the passive avoidance task (10 mg/kg), and there were six animals per group. Rats received daily treatments orally for 28 days for both experiments.
RESULT: Using a passive avoidance task, our data revealed that the rats' memory significantly increased with increasing doses of MS compared to the morphine-treated group. Our findings from LTP recordings showed that LTP was fully blocked by the higher doses of MS.
CONCLUSION: We speculate on the possibility that additional factors were involved in the passive avoidance task because it was an in vivo animal study, while the LTP experiment solely involved brain slices.
Mitragyna speciosa Korth, or better known as ketum, has long been used by traditional folk around Southeast Asia to prevent fatigue from working under hot tropical weather and as a replacement of opium, which can then cause addiction. To date, no findings have been reported of the toxic effect of ketum subchronically (28 days). Hence, the aim of this study was to investigate the toxicity of subchronic effect of standardized methanolic extract of ketum (SMEMS) in Sprague-Dawley rats. Rats were orally administered with 100, 200, and 500 mg/kg of SMEMS for 28 days. Body weights were recorded daily. They were terminated at day 28 to obtain data for hematology, biochemistry, and histopathology of the brain, liver, kidney, lung, heart, sciatic nerve, and spinal cord. The SMEMS affected body weight compared to control group. Biochemistry findings showed that liver and kidney were affected with the abnormal values in AST, creatinine, globulin, glucose, total protein, and urea. However, SMEMS produced toxic effect more to liver, kidney, and lung than other organs as observed histopathologically. The results suggested subchronic exposure of ketum is toxic to the physiology of the animals.
Estrogen replacement therapy (ERT) is the main treatment postmenopausal osteoporosis. However, ERT causes serious side effects, such as cancers and thromboembolic problems. Labisia pumila var. alata (LPva) is a herb with potential as an alternative to ERT to prevent complications of osteoporosis, especially fragility fractures. This study was conducted to determine the effects of LPva on the biomechanical strength of femora exposed to osteoporosis due to estrogen deficiency, using the postmenopausal rat model. Thirty-two female rats were randomly divided into four groups: Sham-operated (Sham), ovariectomized control (OVXC), ovariectomized with Labisia pumila var. alata (LP), and ovariectomized with ERT (Premarin) (ERT). The LPva and ERT were administered via oral gavage daily at doses of 17.5 mg/kg and 64.5 μg/kg, respectively. Following two months of treatment, the rats were euthanized, and their right femora were prepared for bone biomechanical testing. The results showed that ovariectomy compromised the femoral strength, while LPva supplementation to the ovariectomized rats improved the femoral strength. Therefore, LPva may be as effective as ERT in preventing fractures due to estrogen-deficient osteoporosis.
Statins are HMGCoA reductase inhibitors and had been demonstrated to stimulate bone formation in rodents after high oral doses. Observational studies on patients treated with oral statins were varied. Delta-tocotrienol had been found to stimulate the cleavage of HMGCoA reductase and inhibit its activity. Tocotrienols were found to have both catabolic and anabolic effects on bone in different animal models of osteoporosis. The current study aimed to ascertain the effects of delta-tocotrienol and lovastatin combination on biochemical and static bone histomorphometric parameters in a postmenopausal rat model at clinically tolerable doses. 48 Sprague Dawley female rats were randomly divided into 6 groups: (1) baseline control group; (2) sham-operated control group; (3) ovariectomised control group; (4) ovariectomised and 11 mg/kg lovastatin; (5) ovariectomised and 60 mg/kg delta-tocotrienol; (6) ovariectomised and 60 mg/kg delta-tocotrienol + 11 mg/kg lovastatin. These treatments were given daily via oral gavage for 8 weeks. Delta-tocotrienol plus lovastatin treatment significantly increased bone formation and reduced bone resorption compared to the other groups. Therefore, the combined treatment may have synergistic or additive effects and have the potential to be used as an antiosteoporotic agent in patients who are at risk of both osteoporosis and hypercholesterolemia, especially in postmenopausal women.
The development of Breinlia booliati is described in its natural host, Rattus sabanus and in an inbred strain of laboratory albino rat. The growth of the parasite is similar in both the rat hosts. The third moult occurs between six-eight days and the final moult between 24-28 days. Larvae were recovered initially from the skin and carcass. After five weeks, developing stages were seen only in the thoracic and abdominal cavities, the site of development of the adult worms. Worms became sexually mature by 11-12 weeks and there was considerable growth in length of the female worms after this stage.