How can I buy cocaine online in Alor Setar
How can I buy cocaine online in Alor SetarHow can I buy cocaine online in Alor Setar
__________________________
📍 Verified store!
📍 Guarantees! Quality! Reviews!
__________________________
▼▼ ▼▼ ▼▼ ▼▼ ▼▼ ▼▼ ▼▼
▲▲ ▲▲ ▲▲ ▲▲ ▲▲ ▲▲ ▲▲
How can I buy cocaine online in Alor Setar
Official websites use. Share sensitive information only on official, secure websites. This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. In this study, we investigated the antipsychotic-like effect of methanolic extract of Mitragyna speciosa leaf MMS using in vivo and ex vivo studies. In vivo studies comprised of apomorphine-induced climbing behavior, haloperidol-induced catalepsy, and ketamine-induced social withdrawal tests in mice whereas the ex vivo study was conducted utilizing isolated rat vas deferens preparation. Furthermore, MMS inhibited the dopamine-induced contractile response dose-dependently in the isolated rat vas deferens preparations. In conclusion, this investigation provides first evidence that MMS exhibits antipsychotic-like activity with potential to alleviate positive as well as negative symptoms of psychosis in mice. This study also suggests the antidopaminergic activity of MMS that could be responsible for alleviating positive symptoms of psychosis. Keywords: apomorphine, bar test, climbing behavior, haloperidol, ketamine, Mitragyna speciosa , social withdrawal, vas deferens. Psychosis is a devastating mental illness with a high economic burden for many countries. The molecular mechanisms involved in the pathogenesis of psychosis has been extensively studied and reported in the literature Saugstad, In an attempt to reduce the severity of this disease worldwide, many pharmacological treatment options have been constantly developed. Currently available antipsychotics are mainly classified into two categories: typical antipsychotics e. Both classes of antipsychotics possess classical adverse effects profile. For example, extrapyramidal motor disturbances such as acute dystonia and tardive dyskinesia are commonly observed with typical antipsychotics whereas weight gain, ventricular arrhythmias, agranulocytosis are some of the common adverse effects of atypical antipsychotics Howard et al. Therefore, a search for an alternative antipsychotics to effectively treat both positive and negative symptoms with lesser or no adverse effects is a continuous process in the research world. Many researchers have opted to natural resources, mostly herbal remedies in order to develop an efficient therapy Carlini, Mitragyna speciosa Korth. Speciosa , commonly known as ketum or kratom, is an ever green tree from coffee family Rubiaceae mostly found in Thailand and northern Malaysia. Traditionally, M. Moreover, M. Interestingly, M. Mitragynine is the main bioactive compound present in the leaf of M. The pharmacological effects of mitragynine have mainly been explained for its interaction with dopaminergic, adrenergic, and serotonergic receptors Matsumoto et al. It has also been observed that the long-term consumption of M. The claim for the darker skin of habitual user of M. Therefore, it has been postulated that mitragynine darkened the skin by inhibiting dopamine D 2 receptors whereby increasing melanocyte-stimulating substances. Jansen and Prast a proposed if mitragynine proved to be a D 2 receptor antagonist, it could be effectively utilized to treat psychosis. However, based on our thorough literature search, to date there was no report on antipsychotic activity of M. Therefore, the present study was aimed to investigate the antipsychotic-like activity of MMS using in vivo and ex vivo studies. Apomorphine hydrochloride Sigma—Aldrich, USA was dissolved in normal saline containing sodium metabisulphite 0. The different doses of MMS used in the present in vivo study was chosen based on the reported lethal and therapeutic doses of MMS. LD 50 of MMS was found at 4. All drug solutions were prepared fresh in double distilled water. Fresh leaf of M. Fresh M. The methanol extractive was filtered using a filter paper. Methanol solvent from the extractive was removed by evaporation using rotary evaporator. Approximately, g of dried crude methanolic extract of M. Separation was done using an XBridge C18 column 2. The compound elution was carried out using a linear gradient solvent system consisting of solvent A 0. The standard calibration graph was plotted with peak area against the serially diluted mitragynine. The amount of mitragynine in the MMS extract was then quantified accordingly using the linearity equation of standard curve. Swiss albino male mice body weight, 25—30 g and Sprague-Dawley SD male rats body weight, — g , obtained from the Animal Experimental Unit, University of Malaya were used in this study. The animals were housed in a group of four in individually ventilated cages. They were fed with standard laboratory food pellet and allowed access to water ad libitum and maintained under the standard animal laboratory conditions; 12 h light: 12 h dark cycle lights off at The animals were allowed to acclimatize to laboratory conditions for at least 1 week prior to experiments. Immediately after apomorphine injection, the mice were individually placed at the base of corresponding cylindrical cages. The total score of 6 time points during 30 min study every 5 min was calculated and represent as a climbing index. The maximum possible climbing index was Additionally, the duration of climbing by the animal on the wall and lid of metal cages was recorded and represent as a climbing time for 30 min. This test was conducted using a standard bar test as described elsewhere Sanberg, Forepaws of naive mice were placed over a horizontal metal bar diameter: 3 mm , upraised 4. The subcataleptic dose of haloperidol was chosen in order to differentiate potentiation or reversal effect of drugs on haloperidol-induced catalepsy based on earlier published report Pandi et al. The cataleptic behavior of each mouse was recorded at 0 and 60 min after haloperidol injection. The social interaction test was carried out using the method previously described elsewhere Qiao et al. Briefly, mice were housed in eight animals per cage familiar group and acclimatized to a 12 h reversed light cycle lights on at h for 2 weeks prior to the experiments. The mice were introduced to a habituation session prior to the test, whereby each mouse was isolated in the test box for 10 min. During test day, mice were allocated in pairs composed of animal matched for body weight and pertaining to unfamiliar groups different home cages that received the same drug treatment. The bodyweights of the paired mice were matched within 1—2 g of variance. The behavior of each of these pairs was recorded on a camera located above the test box for 10 min for later analysis. All the behavioral observation such as the latency to the first contact and the time spent in social interaction crawling under or over the partner, genital investigation, following, sniffing and grooming the partner of each pairs were analyzed by the trained observer who was blind to the treatment group. Passive contact such as lying or sitting with bodies in contact was not considered as a part of social interaction. The test box was wiped clean with alcohol between each trial to remove the evidence of the presences of other mice. Additionally, the locomotor activity was measured using the method described elsewhere Satow et al. The locomotion of each mice was accessed as the number of lines marked on the floor of the box crossed by the mice during the test. The SD rats were sacrificed by CO 2 inhalation and a pair of vas deferens were immediately isolated and carefully cleaned from connective tissues and blood vessels. The tissue was stretched to 0. The isometric tension g was measured using force transducer connected to the PowerLab recording system AD Instruments, Australia. During this stabilization period, the bath solution was replaced every 15 min. Furthermore, the nature of antagonism was examined in the presences of DMSO 0. As for the ex vivo studies, the concentrations indicated in the text or in the figures represent the final tissue-bath concentration of the drug. The data were analyzed using Graph Pad Prism version 5. The concentration of mitragynine was found to be 4. A Total time spent on the wall of the cage. B The cumulative climbing scores were measured for 30 min after apomorphine administration. C The climbing behavior was scored at 5 min interval after apomorphine treatment. Dopamine exhibited dose-dependent contractile response in epididymal segments of the isolated vas deferens preparation Figure 5. A submaximal dose MMS and haloperidol, a D 2 receptor antagonist dose-dependently shifted the DRC of dopamine to rightward with significant reduction in the maximal response Figures 7A,B. However, the pEC 50 was not significantly altered in both treatment groups Tables 1 and 1. Psychosis animal models are developed based on the neurochemical theory of schizophrenia, primarily involving neurotransmitters such as dopamine and glutamate and it has been used to screen new chemical entities NCEs for potential antipsychotic-like effect Lipska and Weinberger, Apomorphine-induced cage climbing behavior in mice is a widely used animal model to evaluate the antipsychotic potential of NCEs Szechtman, Apomorphine is known to activate both D 1 and D 2 dopamine receptors to exhibit these animal behavior Seeman, ; Stoof and Kebabian, Most of the antipsychotic drugs available in the market are known to suppress the cage climbing behavior by inhibiting the dopaminergic D 2 receptors Szechtman, ; Davis et al. The inhibitory effect of MMS against apomorphine-induced cage climbing behavior suggests the antipsychotic-like effect of MMS mediated by its interaction with the dopaminergic system. Nucleus accumbens and corpus striatum are commonly suggested as major brain regions associated with antipsychotics-induced catalepsy, which seems as a result of blockade associated with dopaminergic neurotransmission. Besides, a drug which increases the dopaminergic neurotransmission suppresses the neuroleptic-induced catalepsy Rang et al. A non-selective dopamine D 2 blocker, for example, haloperidol induced catalepsy by inhibiting the dopamine D 2 receptors in the striatum. The ability of the test compounds to potentiate or inhibit the haloperidol-induced catalepsy in rodents is an indicative of a reduction or augmentation of dopaminergic neurotransmission, respectively. These results suggest that the effective doses of MMS per se possessed antipsychotic-like activity without causing extrapyramidal symptoms like catalepsy. Importantly, the antagonism of dopamine D 2 receptors by the most clinically proven antipsychotic drugs often associated with alleviation of positive symptoms of psychosis such as stereotyped behavior, hallucinations and delusions etc Gardner et al. Therefore, it is postulated that MMS could alleviate positive symptoms of psychosis without causing extrapyramidal side effects like catatonia. To further demonstrate the potential of MMS as an antipsychotic drug for the negative symptoms of psychosis, MMS was tested on ketamine-induced social withdrawal in mice. Ketamine-induced social withdrawal in mice is an established animal model mimicking the negative symptoms of schizophrenic patients Ellenbroek and Cools, The antagonism of NMDA receptors by ketamine on the GABAergic neurons leads to decrease the release of GABA, results in the excessive striatal glutamate release, which stimulates the excess release of dopamine, and 5-HT and this causes hyperactivation of D 2 and 5-HT 2 receptors, respectively, produce symptoms of hyperactivity positive symptom and social interaction deficits negative symptom Homayoun and Moghaddam, ; Chatterjee et al. According to Corbett et al. This finding is in agreement with previously reported data Satow et al. One of the main mechanisms involved to alleviate the negative symptoms of psychosis are mediated through inhibition of 5HT 2A receptors Cepeda and Levine, ; Stone et al. Interestingly, mitragynine the main bioactive constituent of M. Therefore the reversal of ketamine-induced hyperactivity and social withdrawal defects observed with MMS might be mediated through the inhibition of dopamine D 2 receptors and serotonin 5HT 2A receptors. To further elucidate the dopaminergic mediated actions of MMS, ex vivo studies using isolated rat vas deferens preparations were carried out. Dopamine D 2 receptors are predominantly existed in rat vas deferens and dopamine produce contractile response in rat vas deferens Boadle-Biber and Roth, The reference drug, haloperidol also showed similar rightward shift with depression of maxima Figure 7B ; Table 2. These results demonstrate the non-competitive blocking effect of MMS on dopaminergic receptors. To demonstrate the potency of MMS with respect to haloperidol, pEC50 values were compared with haloperidol. These results confirm the antidopaminergic effect of MMS which is responsible for the antipsychotic-like effect of MMS observed in in vivo studies. Effect of haloperidol 1. Dopaminergic D 2 -receptors are the main pharmacological target for treatment of schizophrenia Missale et al. It has been proposed that the positive symptoms are mediated through hyper-activation of mesolimbic dopaminergic D 2 receptors and the negative symptoms by hypo-activation of mesocortical dopaminergic D 1 receptors Toda and Abi-Dargham, Similarly, glutamatergic NMDA receptors blockade produces both positive and negative psychotic symptoms. For example, dizocilpine, ketamine, and phencyclidine NMDA antagonists produce both positive and negative psychotic symptoms in humans Millan, Negative psychotic symptoms are also improved by the blockade of 5HT 2A receptors. Activation of serotonergic 5-HT 2A receptors presents in presynaptic nerve terminals of dopaminergic and glutamatergic neurons inhibit the release of dopamine and glutamate, respectively. Atypical antipsychotics such as clozapine, olanzapine, and risperidone block 5HT 2A receptors thereby enhancing the release of dopamine and glutamate in mesocortical circuit and improve the negative symptoms of schizophrenia Rang et al. Moreover, clozapine and olanzapine also act as 5-HT 2C inverse agonists. Mitragynine has been shown to inhibit 5-HT 2C receptors in in vitro radioligand binding assay Boyer et al. The clinical efficacy of all approved typical and atypical antipsychotic drugs are mainly mediated by blocking post-synaptic D 2 receptors in the brain Seeman, Interestingly, D 2 receptors also act as autoreceptors in the presynaptic nerve terminals of the dopaminergic neurons and inhibit the synthesis and release of dopamine Bello et al. Further studies in this direction are warranted to confirm the actual mechanism of action of MMS. The phytochemical analysis results revealed the presence of mitragynine in MMS by its major peak at a retention time, 3. Mitragynine, being the maximum dominant active alkaloid present in M. Interestingly, mitragynine significantly inhibited the dopamine D 2 and serotonin 5-HT 2 receptors in a radioligand-binding assay Boyer et al. Therefore, it is hypothesized that antipsychotic-like effect of MMS could be mediated by its main bioactive constituent, mitragynine. Further, the antidopaminergic effect of MMS was mediated through the non-competitive antagonism of D 2 receptors in ex vivo study using isolated rat vas deferens preparation. Methanolic extract of Mitragyna speciosa is found to be effective in alleviating positive as well as negative symptoms of psychosis in mouse models and it could be mainly mediated through inhibition of D 2 and 5-HT 2 receptors. Therefore, MMS could be utilized for the development of novel antipsychotic drug to treat both positive and negative symptoms of psychosis. However, further mechanistic studies to demonstrate antipsychotic-like effect of MMS are warranted. The studies in this direction are currently underway in our laboratory. KV performed all behavioral studies, designed the study, accomplished the data analysis and drafted the manuscript. VP conceived, and designed the study and critically revised the manuscript for important intellectual content. TK and DM helped in ex vivo studies. MN critically revised the manuscript for important intellectual content. All authors have read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We are grateful to the management of the University of Malaya for providing financial assistance and necessary infrastructure to carry out this research. As a library, NLM provides access to scientific literature. Front Pharmacol. Find articles by Kamini Vijeepallam. Find articles by Vijayapandi Pandy. Find articles by Thubasni Kunasegaran. Find articles by Dharmani D Murugan. Find articles by Murali Naidu. Received Aug 2; Accepted Nov 16; Collection date Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.
Pengguna Dadah Wanita di Malaysia: Pengalaman Penagihan dan Hubungan Kekeluargaan
How can I buy cocaine online in Alor Setar
Women involvement in drug abuse has adverse impacts not only to the nation but also impose great challenges to achieve stable family structures. Therefore, this article aims to explore the experiences of women drug user in Malaysia with reference to their drug abuse activity and identify the level of family relationship they possess. This research used quantitative method and cross-sectional survey. Data were analyzed using descriptive analysis. The results of the study showed that Analysis of drug using pattern reveals that syabu Finding also showed that majority Findings from this research yielded wide implications to improve drug abuse treatment and rehabilitation programs in an institution, particularly among women drug users in Malaysia. Agensi Anti Dadah Kebangsaan. Diakses pada 2 Januari Alvarez, J. D, Jason, L. Journal of Substance Abuse Treatment. Ayyagari, S. Bahr, S. Journal of Marriage and Family. Blyth, A. Brady, K. American Journal on Addictions. Brown, S. Stress, Vulnerability and Adult Alcohol Relapse. Journal of Studies on Alcohol. Buehler, C. Buelga, S. Current adolescence. Caen: Lower Normandy. Butler, R. Drugs: Education, Prevention and Policy. Chua Yan Piaw. Kaedah dan Statistik Penyelidikan: Kaedah Pendidikan. Kuala Lumpur: McGraw Hill. Chatham, L. Chander, G. Co-occurring Psychiatric Disorders in Women with Addictions. Obstetrics and Gynecology Clinics of North America. Cox, G. Dublin: National Advisory Committee on Drugs. Coyer, S. Journal of Obstetric, Gynecologic, and Neonatal Nursing. Copeland, J. Copello, A. Drug and Alcohol Review. Davis, S. Denier, C. Addictive Behaviors. Asian Social Science. Pertanika Journal of Social Sciences and Humanities. Substance Abuse and Aggressive Behavior among Adolescents. The role of family towards current adolescence challenges: Drug prevention and living without drugs. The Social Science. Fauziah Ibrahim. Bangi: UKM. Asian Social Sciences. Farrell, E. In Pike, B. Friedman, A. Families of Adolescent Drug Abuse Clients. Treatment Research Notes. Gentilello, L. The Journal of Trauma. Gilligan, R. Ferguson, and P. Kenny, Eds. Guo, J. Gruber, K. Hairunnaja Najmuddin. Memahami dan Membimbing Remaja Nakal. Keen, J. Family Practice. Kumpfer, K. L, Alvarado R. Substance use and misuse. Lerner, R. Annual Review of Psychology. Lila, M. Mahmood Nazar Mohamed. Terbitan Persatuan Kaunseling Malaysia. Mackay, R. Social Policy Journal of New Zealand. Malhotra, N. Marketing Research: Applied Orientation. Sydney: Prentice Hall. Mann, K. European Archives of Psychiatry and Clinical Neuroscience. McIntosh, J. International Journal of Drug Policy. Miller, N. Moos, R. Musitu, G. Familia y Adolescencia. Najavits, L. A Research Review. Painter, J. Phillips, J. Poole, N. Girls, Women and Substance Use. Rohayati Derani. Saunders, B. Relapse A Psychological Perspective. British Journal of Addiction. Saxe, G. Gender and Posttraumatic Stress Disorder. Bremner Eds. Boston, MA: Allyn and Bacon. Sheridan, M. The Social Impact of Drug Abuse. Diakses pada 20 Februari Velleman, R. Templeton and A. Vimpani, G. Willson, J. Atlantic Monthly. Williams, R. Parental Awareness of Adolescent Substance Use. Woods, M. Zimmermann, G. Journal of Affective Disorders. This copyright covers the rights to reproduce the article, including reprints, electronic reproductions, or any other reproductions of similar nature. Disclaimer : This website has been updated to the best of our knowledge to be accurate. However, Universiti Teknologi Malaysia shall not be liable for any loss or damage caused by the usage of any information obtained from this web site. Findings from this research yielded wide implications to improve drug abuse treatment and rehabilitation programs in an institution, particularly among women drug users in Malaysia References Agensi Anti Dadah Kebangsaan. Laporan Dadah Malaysia. Downloads PDF. Published Issue Vol. Make a Submission Make a Submission. Database Indexing 1. Powered by. Submission Guide.
How can I buy cocaine online in Alor Setar
Pengguna Dadah Wanita di Malaysia: Pengalaman Penagihan dan Hubungan Kekeluargaan
How can I buy cocaine online in Alor Setar
How can I buy cocaine online in Alor Setar
Pengguna Dadah Wanita di Malaysia: Pengalaman Penagihan dan Hubungan Kekeluargaan
How can I buy cocaine online in Alor Setar
How can I buy cocaine online in Alor Setar
How can I buy cocaine online in Ruse
How can I buy cocaine online in Alor Setar
Buying cocaine online in Sao Paulo
How can I buy cocaine online in Alor Setar