Vesicular monoamine transporter 2 (VMAT2).

Vesicular monoamine transporter 2 (VMAT2) is inhibited by serpine. The density of dopamine D1 receptors in the rat striatum is significantly impacted by serpine (F2,12=8.81, p<0.01). Both acute and chronic reserpine withdrawal do not alter affinity (Kd) for dopamine D1 and D2 receptors [1]. After one day of reserpine administration, the IC50 values in JB6 P+ and HepG2-C8 cells were 43.9 and 54.9 μM, respectively. In the concentration range of 5 to 50 μM, serpine stimulated luciferase activity in a dose-dependent manner; no discernible induction was seen at doses lower than 5 μM. The outcomes demonstrated that reserpine (2.5 to 10 μM) also enhanced Nrf2, HO-1, and NQO1 protein expression. After 7 days of treatment, DNMT1, DNMT3a, and DNMT3b mRNA expression in JB6 P+ cells was lowered by serpine at concentrations ranging from 2.5 to 10 μM in a concentration-dependent manner. The expression of DNMT3a was significantly different (p<0.05) when treated with 10 μM reserpine[2].

Reserpine can be used in animals to develop gastrointestinal ulcer models.

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Reserpine hydrochloride injections given over a long period of 14 days, without an acute phase, at a dose of 0.2 mg/kg, followed by a 48-hour drug withdrawal period will significantly shorten immobility time (F2,18=3.68, p<0.05), but not increase it. Rats' forced swim test (FST) climbing time was (F2,18=4.48, p<0.02) while their swimming time remained unchanged (F2,18=1.78; NS) [1]. In contrast to control animals, vanillylmandelic acid (VMA) was significantly excreted in the urine at a dose of 5 mg/kg body weight of serpine hydrochloride. 5-hydroxyindoleacetic acid (5-HIAA) was found to be excreted at higher rates in reserpine-treated animals than in control animals. Reserpine hydrochloride was found to cause dose-dependent hypotension. At doses of 0.5, 1, 5, 10, and 15 μg/kg, resperpine hydrochloride significantly (p<0.01) lowered blood pressure in comparison to the control group [3].

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The effects of graded doses of zinc sulfate pretreatment on reserpine-induced gastric ulceration and on lysosomal fragility both in vivo and in vitro, were studied in rats. Reserpine treatment (5 mg/kg, i.p., 18 h before sacrifice) induced marked gastric glandular ulceration and elicited the release of free beta-glucuronidase from lysosomes in the gastric mucosa. A similar effect on release of this enzyme from isolated rat hepatic lysosomes was observed after in vitro incubation with reserpine. Zinc sulfate (22, 44 or 88 mg/kg, i.p., 30 h before reserpinization, or 10(-3) M in vitro) inhibited the reserpine-induced response, and zinc sulfate alone (10(-11)--10(-3) M) also stabilized lysosomal membrane permeability to beta-glucuronidase. No direct effect of zinc or reserpine on purified beta-glucuronidase activity was observed. In conclusion, it is postulated that the stabilizing effect of zinc on lysosomal membranes, as manifest by reduced release of beta-glucuronidase from isolated lysosomes, is one of the protective mechanisms of zinc against reserpine-induced ulceration [4].

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This project's aim was to determine the reserpine-induced gastric ulcer preventive effect of polysaccharide of Larimichthys crocea swim bladder (PLCSB) in ICR mice. The anti-gastric ulcer effects of polysaccharide of Larimichthys crocea swim bladder was evaluated in mice model using morphological test, serum levels assay, cytokine levels assay, tissue contents analysis, reverse transcription-polymerase chain reaction (RT-PCR) analysis and western bolt assay. High concentration (50 mg/kg dose) of PLCSB reduced IFN-γ as compared to low concentration (25 mg/kg dose) and control mice. SS and VIP serum levels of PLCSB treated mice were higher than those of control mice, and MOT and SP serum levels were lower than control mice. Gastric ulcer inhibitory index of PLCSB treatment groups mice were much lower than control mice, and the high concentration treated mice were similar to the ranitidine treated mice. The SOD and GSH-Px activities of PLCSB treated mice were higher than control mice, close to normal mice and ranitidine treated mice. PLCSB treated mice also showed the similar contents of NO and MDA to normal group. By RT-PCR and western blot assay, PLCSB significantly induced inflammation in tissues of mice by downregulating NF-κB, iNOS, and COX-2, and upregulating IκB-α. These results suggest that PLCSB showed a good gastric ulcer preventive effect as the gastric ulcer drug of ranitidine. Polysaccharide of Larimichthys crocea swim bladder may be used as a drug material from marine products. [5]

After incubation for 24 h, JB6 P+ cells (1×10~5 cells/10-cm dish) are treated with various concentrations of Reserpine hydrochloride. Whole cell lysates are prepared from the treated cells using radioimmunoprecipitation assay buffer supplemented with a protease inhibitor cocktail, and a BCA kit is used to determine protein concentrations [2].

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a crucial transcription factor that regulates the expression of defensive antioxidants and detoxification enzymes in cells. In a previous study, we showed that expression of the Nrf2 gene is regulated by an epigenetic modification. Rauvolfia verticillata, a traditional Chinese herbal medicine widely used in China, possesses anticancer and antioxidant effects. In this study, we investigated how Nrf2 is epigenetically regulated by reserpine, the main active component in R. verticillata, in mouse skin epidermal JB6 P+ cells. Reserpine induced ARE (antioxidant response element)-luciferase activity in HepG2-C8 cells. Accordingly, in JB6 P+ cells, it upregulated the mRNA and protein levels of Nrf2 and its downstream target genes heme oxygenase-1 (HO-1) and [2]
Nad(p)h: quinone oxidoreductase 1 (NQO1), while it only increased the protein level of UDP-glucuronosyltransferase 1A1 (UGT1A1). Furthermore, reserpine decreased the TPA (12-O-tetradecanoylphorbol-13-acetate)-induced colony formation of JB6 cells in a dose-dependent manner. DNA sequencing and methylated DNA immunoprecipitation further demonstrated the demethylation effect of reserpine on the first 15 CpGs of the Nrf2 promoter in JB6 P+ cells. Reserpine also reduced the mRNA and protein expression of DNMT1 (DNA methyltransferase 1), DNMT3a (DNA methyltransferases 3a), and DNMT3b (DNA methyltransferases 3b). Moreover, reserpine induced Nrf2 expression via an epigenetic pathway in skin epidermal JB6 P+ cells, enhancing the protective antioxidant activity and decreasing TPA-induced cell transformation. These results suggest that reserpine exhibits a cancer preventive effect by reactivating Nrf2 and inducing the expression of target genes involved in cellular protection, potentially providing new insight into the chemoprevention of skin cancer using reserpine. [2]

Reserpine treatment (5 mg/kg) produced a significant increase in the urinary excretion of VMA, 5-HIAA and HVA while RMN at doses of equal to and double the equimolar doses of reserpine (5 and 10 mg/kg) produced significant increase in VMA and 5-HIAA excretion without producing any effect on HVA excretion compared to control animals. Reserpine in the dose range of 0.5 to 15 microg/kg produced significant reduction in blood pressure compared to control. RMN was also found to produce significant decrease in blood pressure at doses of 10, 25 and 50 microg/kg body weight in comparison to control. The results indicated peripheral depletion of biogenic amines by RMN without affecting the central stores of the amines. [3]

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Reserpine can be used for establishing pharmacological model of Gastrointestinal ulcer
Rats: Wistar rats • Male • 200-290 g
Administration route: 5 mg/kg • intraperitoneal injection • euthanized rats after 18 hours of injection
Mice: ICR mice • Male • 7 weeks old
Administration route: 10 mg/kg • intraperitoneal injection • once a day, for a total of 3 days

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Reserpine can be used for establishing pharmacological model of depression
Rats: Wistar rats • Male • 120-150 g
Administration route: 0.5 mg/kg • intraperitoneal injection • once a day, for a total of 14 days
Mouse: C57BL/6 mice • Male • 7 weeks old
Administration route: 0.5 mg/kg • intraperitoneal injection • once a day, for a total of 10 days

Reserpine is an inhibitor of the vesicular monoamine transporter 2 (VMAT2) and monoamine releaser, so it can be used as a pharmacological model of depression. In the present paper, we investigated the behavioral and neurochemical effects of withdrawal from acute and repeated administration of a low dose of reserpine (0.2 mg/kg) in Wistar Han rats. We demonstrated the behavioral and receptor oversensitivity (postsynaptic dopamine D1) during withdrawal from chronic reserpine. It was accompanied by a significant increase in motility in the locomotor activity test and climbing behavior in the forced swim test (FST). Neurochemical studies revealed that repeated but not acute administration the a low dose of reserpine triggered opposing adaptive changes in the noradrenergic and serotonin system function analyzed during reserpine withdrawal, i.e. 48 h after the last injection. The tissue concentration of noradrenaline was significantly decreased in the hypothalamus and nucleus accumbens only after repeated drug administration (by about 20% and 35% vs. control; p<0.05, respectively). On the other hand, the concentration of its extraneuronal metabolite, normetanephrine (NM) increased significantly in the VTA during withdrawal both from acute and chronic reserpine. The serotonin concentration was significantly reduced in the VTA after chronic reserpine (by about 40% vs. the control group, p<0.05) as well as its main metabolite, 5-HIAA (by about 30% vs. control; p<0.05) in the VTA and hypothalamus. Dopamine and its metabolites were not changed after acute or chronic reserpine administration. In vivo microdialysis studies clearly evidenced the lack of the effect of a single dose of reserpine, and its distinct effects after chronic treatment on the release of noradrenaline and serotonin in the rat striatum. In fact, the withdrawal from repeated administration of reserpine significantly increased an extraneuronal concentration of noradrenaline in the rat striatum but at the same time produced a distinct fall in the extraneuronal serotonin in this brain structure. On the basis of the presented behavioral and neurochemical experiments, we suggest that chronic administration of reserpine even in such low dose which not yet acted on the release of monoamines but produced an inhibition of VMAT2 caused a long-lasting disadvantageous effect of plasticity in the brain resembling depressive disorders. [1]

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Treatment with the antihypertensive agent reserpine depletes monoamine levels, resulting in depression. In the present study, we evaluated the antidepressant effects of Gyejibokryeong-hwan (GBH), a traditional Korean medicine, in a mouse model of reserpine-induced depression. Mice were treated with reserpine (0.5 mg·kg-1, i.p.) or phosphate-buffered saline (PBS, i.p., normal) once daily for 10 days. GBH (50, 100, 300, and 500 mg·kg-1), PBS (normal, control), fluoxetine (FXT, 20 mg·kg-1), or amitriptyline (AMT, 30 mg·kg-1) was administered orally 1 h prior to reserpine treatment. Mouse behavior was examined in the forced swim test (FST), tail suspension test (TST), and open-field test (OFT) following completion of the treatment protocol. Administration of GBH reduced immobility time in the FST and TST and significantly increased the total distance traveled in the OFT. Plasma serotonin levels were significantly lower in control mice than in normal mice, although these decreases were significantly attenuated to a similar extent by treatment with GBH, FXT, or AMT. Reserpine-induced increases in plasma corticosterone were also attenuated by GBH treatment. Moreover, GBH attenuated reserpine-induced increases in interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α mRNA expression in the hippocampus. In addition, GBH mice exhibited increased levels of brain-derived neurotrophic factor (BDNF) and a higher ratio of phosphorylated cAMP response element-binding protein (p-CREB) to CREB (p-CREB/CREB) in the hippocampus. Our results indicated that GBH can ameliorate depressive-like behaviors, affect the concentration of mood-related hormones, and help to regulate immune/endocrine dysfunction in mice with reserpine-induced depression, likely via activation of the BDNF-CREB pathway. Taken together, these findings indicate that GBH may be effective in treating patients with depression. [7]

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Depression is a major psychological disorder that contributes to global health problem. This study aimed to evaluate the anti-depressant effect of Cerebrolysin (CBL) in Reserpine-induced depressed rats, its effect on oxidative stress, inflammation, regulatory cyclic AMP-dependent response element binding protein (CREB)/brain derived neurotropic factor (BDNF) signaling pathways, brain monoamines and histopathological changes was assessed. Rats received either the vehicle or Reserpine (0.5 mg/kg, i.p.) for 14 days. The other three groups were pretreated with CBL (2.5, 5 ml/kg; i.p.) or fluoxetine (FLU) (5 mg/kg, p.o.), respectively for 14 days, 30 min before reserpine injection. Then analyses were conducted. CBL reversed Reserpine-induced reduction in latency to immobility and prolongation of immobility time in the forced swimming test (FST), reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced tumor necrosis factor-alpha (TNF-ɑ), and elevated BDNF cortical and hippocampal brain contents. CBL elevated protein kinase A (PKA) and nuclear factor kappa-B (NF-κB) cortical and hippocampal protein expressions. CBL also ameliorated alterations in mRNA expressions of protein kinase B (AKT), CREB and BDNF in the cortical and hippocampal tissues. CBL elevated nor-epinephrine (NE), serotonin (5-HT), and dopamine (DA) and reduced 5-Hydroxyindoleacetic acid (5-HTAA), 3,4-Dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) cortical and hippocampal contents. CBL effects were in parallel to those observed with the standard anti-depressant drug, FLU. This study shows that CBL exerted anti-depressant effect evidenced by attenuation of oxidative stress and inflammation as well as enhancement of neurogenesis, amelioration of monoaminergic system and histopathological changes. [8]

Absorption, Distribution and Excretion
Reserpine is extensively metabolized to inactive compounds. It is slowly excreted via the urine and feces.
In man, after oral admin of 0.25 mg (3)H-reserpine, tritium was rapidly absorbed into the blood, reaching a peak within 1-2 hr. Radioactivity was tightly bound to red blood cells and remained constant over a 96 hr period. ... Six percent of the dose was excreted in the urine by 24 hr, mainly as trimethoxybenzoic acid; but radioactivity was still detectable in plasma, urine, and feces 11-12 days after drug admin.
PARENTERAL ADMIN OF RESERPINE PRODUCES GREATER CONCN IN NEONATAL RAT BRAIN THAN IN ADULT ANIMALS ... PARALLELED BY GREATER DEPLETION OF NOREPINEPHRINE IN INFANT THAN IN ADULT BRAIN. THIS MAY BE DUE TO LESSER CAPACITY OF RAT NEONATES TO METABOLIZE RESERPINE ... MIGHT ALSO EXPLAIN HIGHER PLASMA & TISSUE LEVELS IN HUMAN ADULTS.
RESERPINE LEAVES BLOOD WITHIN FEW MIN AFTER IV INJECTION & ACCUMULATES IN FATTY TISSUES ... MAX CONCN IN 4-6 HR. LIVER ALSO ACCUMULATES RESERPINE. MOST OF SINGLE DOSE HAS LEFT FAT & LIVER IN 48 HR. BRAIN RETAINS ... RESERPINE & ... METABOLITES ... 5 DAYS AFTER SINGLE DOSE.
... CLAIMED TO BE ADEQUATELY ABSORBED FROM GI TRACT, BUT DIFFERENCE IN EFFICACY OF ORAL & IV DOSES RAISES DOUBTS ABOUT ADEQUACY OF ABSORPTION. ... HAS LONG LATENCY OF ONSET & PROLONGED DURATION OF ACTION.
For more Absorption, Distribution and Excretion (Complete) data for RESERPINE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
YIELDS 3,4,5-TRIMETHOXYBENZOIC ACID IN RAT, CAT, MOUSE;
YIELDS METHYL RESERPATE IN RAT, CAT;
IDENTIFIED METABOLIC PRODUCTS ARE RESERPIC ACID, SYRINGIC ACID, & SYRINGOYL METHYL RESERPATE.
In rats, orally administered reserpine is rapidly hydrolysed to methyl reserpate; and in mice, orally or intravenously administered reserpine is metabolized to trimethoxybenzoic acid. In rats, methyl reserpate appears to be formed in the intestinal mucosa. Trimethoxybenzoic acid is rapidly eliminated in the urine of mice.

Route of Elimination: Reserpine is extensively metabolized to inactive compounds. It is slowly excreted via the urine and feces.

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Biological Half-Life
In man, after oral /dose/ of 0.25 mg (3)H-reserpine ... disappearance of radioactivity in plasma was biphasic: first component had half-life of 4.5 hr, and the second, 271 hr.

Toxicity Summary
IDENTIFICATION: Reserpine is an antihypertensive agent. Origin of the substance: An alkaloid from the roots of certain species of Rauwolfia, usually Rauwolfia serpintina or R. vomitoria. Reserpine can also be synthesized. Color: White or pale buff to slightly yellow colored. It is insoluble in water, freely soluble in chloroform and acetic acid, and very slightly soluble in alcohol and ether. Bioavailability: The reported bioavailability after oral ingestion is approximately 50%. Indications: Description: Hypertension; Raynaud's phenomenon; possibly for prevention of attacks of familial Mediterranean fever. Possibly for treatment of thyroid storm not responsive to standard therapy. HUMAN EXPOSURE: Main risks and target organs: The main risks associated with reserpine poisoning are central nervous system depression, the development of psychiatric depression, cardiovascular toxicity, and gastrointestinal irritation. The main target organs are the central nervous system, cardiovascular system, and gastrointestinal tract. Summary of clinical effects: The clinical effects include sedation and lethargy, which can rarely progress to coma, and gastrointestinal irritation which includes nausea, vomiting, and abdominal cramping. Gastrointestinal irritation can be severe and result in ulceration, perforation, and hemorrhage. Psychiatric depression can be severe and lead to suicidal thoughts and there can be nightmares, and vertigo. Cardiovascular effects include hypotension and bradycardia. Nasal congestion and flushing are also frequent. Hypothermia has also been described. These effects are generally more common with poisonings. The most commonly reported effects were facial flushing, lethargy which rarely progressed to coma, hypotension and bradycardia. Death has been described from hypotension in two patients. Contraindications: Absolute: Pregnancy, psychiatric depression, active peptic ulcer disease; ulcerative colitis; Parkinson's disease; pheochromocytoma and hypersensitivity to any rauwolfia alkaloid Relative contraindications where the use of reserpine should be undertaken with caution and started with lower doses: Elderly patients, cardiac arrhythmias; myocardial infarction; renal insufficiency and asthma. Routes of entry: Oral: The most common route of administration and poisoning. Parenteral: Intramuscular injection has been used for the urgent treatment of hypertension. Intra-arterial injection has been described in Raynaud's syndrome, but appears to be ineffective. Absorption by route of exposure: The reported bioavailability is approximately 50% to 70% after oral ingestion. Absorption is relatively rapid, with peak concentrations achieved approximately 1 to 2 hours after administration of an oral solution. Slower absorption, with peak concentrations at 2 to 4 hours has also been reported. Distribution by route of exposure: The volume of distribution has not been reported. It is widely distributed into the brain, liver, spleen, kidney, and adipose tissue. Reserpine binds to red blood cells and in the peripheral neuron at its site of action. It is reported not to bind to plasma protein. Reserpine crosses the placental barrier, and is found in breast milk. An initial half-life of distribution of approximately 4 to 5 hours is observed after oral administration. Biological half-life by route of exposure: Reserpine can be described using a two compartmental pharmacokinetic model. The elimination half-life ranges from 45 to 168 hours in plasma. Because of binding to red blood cells, the terminal elimination half-life is longer when whole blood levels is measured, and has been reported to be 386 hours. The half-life is longer in patients with renal insufficiency. The elimination half-life was significantly prolonged in patients with creatinine clearance values of less than 10 mL/min. Metabolism: Hepatic metabolism accounts for less than 50% of the elimination of reserpine, with the remainder being eliminated in the feces, and some unmetabolized reserpine and metabolites being eliminated in the urine. In man, metabolites are methylreserpate and trimethoxybenzoic acid. Metabolism may be more important with intramuscular administration. Elimination by route of exposure: The elimination of reserpine and its metabolites in the feces ranges from 30% after intramuscular administration to approximately 60% after oral administration, primarily as unmetabolized reserpine, over a 4 day period. Over the same time period approximately 8% of the administered dose was recovered in the urine, primarily as the trimethoxybenzoic acid metabolite. Pharmacology and toxicology: Mode of action: Toxicodynamics: The mechanism of reserpine's toxic effects is similar to the mechanism of it's pharmacologic effects. Reserpine inhibits normal sympathetic activity in both the CNS and peripheral nervous system by binding to catecholamine storage vesicles. This prevents the normal storage of catecholamines and serotonin in the nerve cell, with the result being catecholamine depletion. Reserpine has also been described as inhibiting catecholamine synthesis by blocking the uptake of dopamine into the storage vesicle. Pharmacodynamics: Reserpine inhibits normal sympathetic activity by decreasing the storage of catecholamines at the pre-synaptic, CNS, and peripheral neuron. Reserpine binds to the storage vesicles, causing catecholamines to leak into the synapse so that they are not available for release when the pre-synaptic neuron is stimulated. The process appears to affect serotonin storage in a similar manner. These actions result in a reduction in both cardiac output and peripheral vascular resistance with long term therapy, which takes approximately 3 weeks to develop after the initiation of therapy. Heart rate and renin concentrations decrease, and there is sodium and water retention. Human data: Adults: There are few reported cases of reserpine poisoning in adult patients. In a series of 151 cases reported from the United States from 1959 to 1960 only 4% were adults. Nausea, vomiting, hypotension, sedation, and coma were described in these patients. Psychiatric depression is historically the most important adverse effect associated with the chronic administration of reserpine for the treatment of hypertension. The depression is most common with higher daily doses, and the frequency is significantly decreased when the dose is lower. The depression is often severe, can occur in patients without a prior history of depressive illness, and may last for months after reserpine is discontinued. Children: Most of the reported cases of reserpine poisoning have been in children. One hundred forty two of the 151 cases of rauwolfia poisoning were in children less than 13 years of age. Approximately 40% of the cases had some symptoms, Mild CNS depression such as lethargy or sedation was the most common symptom, and facial flushing the next most common. Hospitalization for toxicity was needed in 24 of the 142 pediatric cases. Nausea, vomiting, hypotension and vertigo were also described. Individual cases of toxicity include information about potential doses of reserpine ingested and the time course of toxicity. A 20 month old male who ingested reserpine had symptoms of lethargy, flushing, rapid pulse rate and slowed respiration. Within 21 hours the symptoms had primarily resolved without any specific therapy other than a cathartic. A mild leukocytosis resolved within 2 weeks. Three cases of reserpine ingestion in children between 30 months and 4 years of age, who ingested large doses of reserpine (2 cases), and an unknown dose (1 case), demonstrated a wide range of toxicity. All cases had some lethargy and CNS depression which progressed to coma. Bradycardia and hypothermia was also documented in all cases, while the youngest child also had an episode of hypertension and tachycardia starting about 10 hours after ingestion. Carcinogenicity: There does not appear to be an association between reserpine administration and cancer. Teratogenicity: In 48 cases of mothers who had taken reserpine during their first trimester of pregnancy, the incidence of birth defects was 8%, higher than expected, although no major types of malformations were seen. There was no increased risk of birth defects in women who ingested reserpine at any time during their pregnancy. Interactions: The following drugs have been reported to interact with reserpine: Alcohol and CNS depressant drugs: increased sedation Nonsteroidal anti-inflammatory drugs: increased risk of gastric irritation Drugs with antimuscarinic actions: increased gastric acid secretion Beta-adrenergic blocking agents: additive beta adrenergic blockade Bromocriptine: increased serum prolactin and decreased bromocriptine activity Digitalis glycosides: possible increase in bradycardia and arrhythmias Quinidine: possible increase in arrhythmias Estrogens: decrease antihypertensive effects of reserpine Drugs causing extrapyramidal adverse effects: potentiate extrapyramidal activity Antihypertensive agents: hypotension Levodopa: decreased efficacy of levodopa Monoamine oxidase inhibitors: increased CNS depression or increased blood pressure and CNS stimulation Sympathomimetics: decreased effects of reserpine Main adverse effects: The main adverse effects described with the therapeutic administration of reserpine include lethargy and sedation, psychiatric depression, hypotension, nausea, vomiting, abdominal cramping, gastric ulceration, nightmares or vivid dreams, bradycardia, and bronchospasm (in asthmatics) Much less common are symptoms of skin rash or itching, Parkinsonian effects, and thrombocytopenia. Adverse effects are more common with daily doses of reserpine of 0.5 mg or greater. The lethargy and sedation is more common when other CNS depressant drugs are being used concurrently. Adverse reactions were reported in 26 of 231 hospitalized patients who received reserpine. Three reactions after intramuscular reserpine doses of 0.5 mg or greater were considered life-threatening (hypotension in 2 patients, cerebral edema in 1 patient), but no deaths were attributed to reserpine. Bronchospasm has been described when reserpine is administered to asthmatics, and may be relatively common. A case of withdrawal psychosis has been described. Clinical effects: Acute poisoning: Ingestion: Poisoning with reserpine most commonly results in lethargy, sedation, and infrequently results in coma. Other effects include psychiatric depression, hypothermia, facial flushing, nausea, vomiting, abdominal cramping, and cardiovascular toxicity including hypotension and bradycardia. Parenteral exposure: After intramuscular injection of therapeutic doses of reserpine, hypotension, bronchospasm, lethargy and sedation have occurred. These effects are most commonly secondary to larger doses, and are not expected to be any different than the adverse effects associated with oral reserpine administration. Chronic poisoning: Ingestion: The development of psychiatric depression, which can be severe, and gastric ulceration and hemorrhage are the most severe adverse effects of chronic reserpine therapy. Nasal congestion, dry mouth, diarrhea, abdominal pain, lethargy, Parkinsonian features, breast enlargement, galactorrhea, impotence, sodium retention, peripheral edema, and weight gain have been reported much less commonly. Parenteral exposure: The administration of intramuscular reserpine results in adverse effects similar to those seen with oral administration. They are more commonly reported following intramuscular injection because of the larger doses administered and the increased bioavailability associated with this route. Course, prognosis, cause of death: Symptoms of toxicity develop over the first 4 hours after ingestion. Symptoms generally resolve over 18 to 24 hours. The prognosis is generally very good, and patients recover without sequelae. The psychiatric depression can take months to resolve. Two deaths following reserpine poisoning have been reported in the Russian literature. Both cases were adults who died of cardiovascular collapse and multi-organ system failure in the first few days after ingestion. Systematic description of clinical effects: Cardiovascular: Cardiovascular effects associated with reserpine poisoning are relatively uncommon, with only two cases of hypotension reported in a total of 151 patients. Bradycardia is also described, and there is one case of tachycardia and hypertension which developed approximately 10 hours after ingestion. Angina-like symptoms, and dysrhythmias are possible when reserpine is administered to patients taking a digitalis glycoside, quinidine or procainamide. Respiratory: Upper respiratory bronchospasm and nasal congestion may occur. Neurological: CNS: The most common symptoms with poisoning are lethargy and sedation, which occurred in 44% of 151 rauwolfia poisonings. Coma is much less common. A decrease in body temperature may develop. With poisonings, psychiatric depression may occur, however, it is more commonly described with chronic reserpine use. Additional CNS effects include nightmares and vivid dreams, vertigo, headache, dizziness, nervousness, anxiety, and rarely deafness. The development of extrapyramidal symptoms including dystonia and Parkinson's symptoms is reported, though it is not clear whether these develop after poisonings, or only with chronic therapy. There is a case of reserpine withdrawal psychosis which developed over 1 week after a 66 year old female ceased the daily ingestion of 3 mg of reserpine. Reserpine lowers the seizure threshold, however, clonic seizures have been described in only one case. Peripheral nervous system: The effects of reserpine on the peripheral nervous system catecholamine stores would be expected to diminish the responsiveness of the reserpine poisoned patients to indirect acting vasoconstrictors such as dopamine. Direct acting agents such as phenylephrine, metaraminol, and norepinephrine are suggested as vasoconstrictors for the treatment of hypotension which is unresponsive to intravenous fluids. Autonomic nervous system: No direct effects are described. The development of gastrointestinal ulceration is described as being due to increased gastric acid secretion which could be due to changes in autonomic nervous system function. Skeletal and smooth muscle: Gastric cramping is described. Muscle weakness can also occur. Gastrointestinal: Abdominal cramping, nausea, vomiting. Gastric ulceration and hemorrhage are less common. Urinary: Other: Painful or difficult urination is described as a rare adverse effect of chronic therapy. Endocrine and reproductive systems: Chronic therapy is associated with breast engorgement and galactorrhoea. Gynecomastia, increased prolactin concentrations, decreased libido and impotence are also potential adverse effects of chronic therapy. It is not known whether these effects occur with acute poisonings. Dermatological: Facial flushing, rashes, and pruritis. Eye, ear, nose, throat: local effects: Nasal congestion, sialorrhea, slight decrease in color vision, conjunctival injection, lacrymation, and miosis. Hematological: Thrombocytopenic purpura Immunological: Angioimmunoblastic lymphadenopathy Metabolic: Fluid and electrolyte disturbances: Sodium and water retention with the development of edema. Allergic reactions: There is cross sensitivity with reserpine among the different rauwolfia substances. Reports of allergic reactions were not identified. Special risks: The administration of reserpine at the end of pregnancy can cause nasal congestion, respiratory distress, cyanosis, poor feeding, and lethargy in the newborn infant. Reserpine is accepted therapy during breastfeeding. ANIMAL/PLANT STUDIES: Carcinogenicity: Studies in rats and mice using doses at least 100 fold greater than the usual human dose have demonstrated an increased incidence of mammary fibroadenomas, malignant tumors of the seminal vesicles, and malignant adrenal medullary tumors. Teratogenicity: Reserpine administered in large doses has been demonstrated to be teratogenic in rats and guinea pigs. Mutagenicity: Recent studies have suggested a lack of mutagenic, genotoxic, and recombinogenic effects.
Reserpine's mechanism of action is through inhibition of the ATP/Mg²⁺ pump responsible for the sequestering of neurotransmitters into storage vesicles located in the presynaptic neuron. The neurotransmitters that are not sequestered in the storage vesicle are readily metabolized by monoamine oxidase (MAO) causing a reduction in catecholamines.

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Hepatotoxicity
Serum aminotransferase elevations during reserpine therapy are uncommon, but specific rates of such elevations in comparison to placebo treatment have not been reported. Despite many decades of use, reserpine has been implicated in few instances of clinically apparent acute liver injury, and none of them were particularly convincing. Published cases were marked by jaundice and abdominal pain arising a year after starting reserpine, but in combination with other known hepatotoxic agents (dihydrazine, phenobarbital, quinidine). The few cases that have been reported were self-limiting and resolved within a few months of stopping therapy. The last case of suspected reserpine associated liver injury was published more than 50 years ago.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of reserpine during breastfeeding and it might adversely affect the breastfed infant, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Although not well documented, reserpine is said to cause nasal stuffiness and increased tracheobronchial secretions in breastfed infants.
◉ Effects on Lactation and Breastmilk
Reserpine has reportedly caused galactorrhea and has been used to increase breastmilk production, although it is obsolete for this use.

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Protein Binding
62%

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Toxicity Data
LD50: 420 mg/kg (Oral, Rat) (A308)
LD50: 44 mg/kg (Intraperitoneal(parenteral), Rat) (A308)
LD50: 15 mg/kg (Intravenous(parenteral), Rat) (A308)
LD50: 200 mg/kg (Oral, Mouse) (A308)
LD50: 52 mg/kg (Subcutaneous(parenteral), Mouse) (A308)
LD50: 7 mg/kg (Intraperitoneal(parenteral), Rabbit) (A308)

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Interactions
NINE MALE WISTAR RATS GIVEN 16 MG/KG OF DIET WERE PROTECTED AGAINST CARCINOGENIC EFFECTS OF NITROSODIETHYLAMINE (50 MG/L IN THE DRINKING-WATER). FIFTEEN DAILY SC INJECTIONS OF RESERPINE IN RATS FROM AGE OF 50 DAYS, FOLLOWED AT AGE OF 55 DAYS BY SINGLE IV INJECTION OF DIMETHYLBENZ[A]ANTHRACENE, RESULTED IN INHIBITORY ACTION ON MAMMARY TUMOR PRODUCTION OF DIMETHYLBENZ[A]ANTHRACENE ALONE (81% VS 100%).
POTENTIATES PARATHION & CARBARYL TOXICITY IN RATS.
/Reserpine/ may sensitize anesthetics and interfere with cardiovascular adjustments during surgery.
When Rauwolfia alkaloids are administered with diuretics or other hypotensive agents, the hypotensive effects of the alkaloids may be increased. /Rauwolfia alkaloids/
For more Interactions (Complete) data for RESERPINE (13 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 420 mg/kg
LD50 Rat ip 44 mg/kg
LD50 Rat sc 25 mg/kg
LD50 Rat iv 15 mg/kg
For more Non-Human Toxicity Values (Complete) data for RESERPINE (11 total), please visit the HSDB record page.

[1]. Withdrawal from repeated administration of a low dose of reserpine induced opposing adaptive changes in the noradrenaline and serotonin system function: a behavioral and neurochemical ex vivo and in vivo studies in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:146-54.

[2]. Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway. AAPS J. 2016 May;18(3):659-69.

[3]. Reserpine methonitrate, a novel quaternary analogue of reserpine augments urinary excretion of VMA and 5-HIAA without affecting HVA in rats. BMC Pharmacol. 2004 Nov 16;4:30.

[4]. Reserpine-induced gastric ulcers: protection by lysosomal stabilization due to zinc. Eur J Pharmacol. 1980 Feb;61(4):347-53.

[5]. Preventive Effect of Polysaccharide of Larimichthys crocea Swim Bladder on Reserpine Induced Gastric Ulcer in ICR Mice. Korean J Physiol Pharmacol. 2014 Apr;18(2):183-90.

[6]. Mechanism of ulcerogenic activity of reserpine in albino rats. Eur J Pharmacol. 1974 Jul;27(2):269-71.

[7]. Antidepressant-Like Effects of Gyejibokryeong-hwan in a Mouse Model of Reserpine-Induced Depression. Biomed Res Int. 2018 Jun 26;2018:5845491.

[8]. Anti-depressant effect of cerebrolysin in reserpine-induced depression in rats: Behavioral, biochemical, molecular and immunohistochemical evidence. Chem Biol Interact. 2021 Jan 25;334:109329.

Therapeutic Uses
Adrenergic Uptake Inhibitors; Antihypertensive Agents; Antipsychotic Agents; Sympatholytics
RESERPINE ... FOUND TO REDUCE HEART RATE, TREMOR, & STARE IN HYPERTHYROIDISM & RELIEVE PALPITATION, ANXIETY, & TENSION.
ONLY IMPORTANT APPLICATION OF CARDIOVASCULAR EFFECTS OF RESERPINE IS IN TREATMENT OF HYPERTENSION ... IT IS OCCASIONALLY USED IN MANAGEMENT OF RAYNAUD'S SYNDROME.
IV ... USEFUL IN ... SEVERE HYPERTENSION & HYPERTENSIVE EMERGENCIES.
For more Therapeutic Uses (Complete) data for RESERPINE (18 total), please visit the HSDB record page.

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Drug Warnings
... Should not be given to patients with a history of depression and, if depressive symptoms appear, the drug should be discontinued. Reserpine may incr gastric acid secretion and should be used cautiously in patients with history of peptic ulcers. If symptoms suggest recurrence of the ulcer, the drug should be discontinued.
WHEN GIVEN PARENTERALLY FOR TREATMENT OF ECLAMPSIA, RESERPINE PASSES THROUGH PLACENTAL CIRCULATION & MAY CAUSE DROWSINESS, NASAL CONGESTION, CYANOSIS, & ANOREXIA IN NEWBORN INFANT. SODIUM & WATER RETENTION MAY OCCUR IF DIURETIC IS NOT GIVEN CONCOMITANTLY.
BECAUSE OF SERIOUSNESS OF SIDE EFFECTS, RESERPINE IS NO LONGER MUCH USED AS TRANQUILIZER.
... CONTRAINDICATED IN ULCERATIVE COLITIS BECAUSE OF INCR IN BOWEL MOBILITY.
For more Drug Warnings (Complete) data for RESERPINE (23 total), please visit the HSDB record page.

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Pharmacodynamics
Reserpine is an adrenergic blocking agent used to treat mild to moderate hypertension via the disruption of norepinephrine vesicular storage. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance.

608.273

C, 65.12; H, 6.62; N, 4.60; O, 23.66

50-55-5

Reserpine hydrochloride;16994-56-2;Reserpine-d9;84759-11-5; Reserpine;50-55-5; 1263-94-1 (phosphate)

5770

White to light yellow solid powder

1.3±0.1 g/cm3

700.1±60.0 °C at 760 mmHg

265ºC (dec.)

377.2±32.9 °C

0.0±2.2 mmHg at 25°C

1.620

4.05

1

10

10

44

1000

6

O(C([H])([H])[H])[C@@]1([H])[C@@]([H])(C([H])([H])[C@]2([H])C([H])([H])N3C([H])([H])C([H])([H])C4C5C([H])=C([H])C(=C([H])C=5N([H])C=4[C@@]3([H])C([H])([H])[C@]2([H])[C@]1([H])C(=O)OC([H])([H])[H])OC([H])([H])[H])OC(C1C([H])=C(C(=C(C=1[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])=O

QEVHRUUCFGRFIF-MDEJGZGSSA-N

InChI=1S/C33H40N2O9/c1-38-19-7-8-20-21-9-10-35-16-18-13-27(44-32(36)17-11-25(39-2)30(41-4)26(12-17)40-3)31(42-5)28(33(37)43-6)22(18)15-24(35)29(21)34-23(20)14-19/h7-8,11-12,14,18,22,24,27-28,31,34H,9-10,13,15-16H2,1-6H3/t18-,22+,24-,27-,28+,31+/m1/s1

methyl (1R,15S,17R,18R,19S,20S)-6,18-dimethoxy-17-(3,4,5-trimethoxybenzoyl)oxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate

Serpasil; Reserpine; Serpalan; Reserpine; phosphate; Raudixin; Apoplon; Alserin; Hypersil; Sandril;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~41.07 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)