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Levocabastine

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Last Updated: 16 December 2020

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General | Latest Info

Levocabastine

Chemical and physical data
3D model ( JSmol )Interactive image
FormulaC 26 H 29 F N 2 O 2
Molar mass420.528 gmol 1
Clinical data
AHFS / Drugs.comMicromedex Detailed Consumer Information
ATC codeR01AC02 ( WHO ) S01GX02 ( WHO )
Pregnancy categoryAU : B3, US : C (Risk not ruled out),
Routes of administrationOphthalmic, intranasal
Trade namesLivostin
Identifiers
CAS Number79516-68-0 Y
ChEMBLChEMBL1201312 N
ChemSpider16736421 Y
CompTox Dashboard ( EPA )DTXSID1048548
DrugBankDB01106 Y
IUPHAR/BPS1586
KEGGD08117 Y
PubChem CID54385
UNIIH68BP06S81
Legal status
Legal statusUS : -only , In general: (Prescription only)

Levocabastine absorption from the eye occurs within 1-2 hours. Bioavailability from topical ocular administration ranges from 30 % to 60 %. Steady-state plasma levels after application of 0. 05 % ophthalmic suspension one drop three times a day are 1. 6 g / l. Drug has plasma protein binding of approximately 65 %. The half-life of levocabastine is fairly long: between 35 and 40 hours regardless of route of administration. There is very little hepatic metabolism, with about 75 % of drug excrete unchanged in urine and 10-20 % unchanged in feces. The recommended dosage is one drop in each Eye bid to qid Eye drops administered regularly do not suppress histamine-induced skin wheal and flare.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

BRAND NAME(S): Livostin

Medication USE | HOW TO USE | Side Effects | Precautions | Drug Interactions | Overdose | Notes | miss Dose | Storage HOW TO USE: If you are using another kind of eye medication, wait at least 5-10 minutes between applying each medication. USE eye drops before eye ointments TO allow drops TO enter the eye. TO apply eye medication, wash your hands first. TO avoid contamination, do not touch the dropper tip or let it touch your eye or any other surface. USE in eyes only. Do not swallow. If you are wearing contact lenses, remove them before using eye drops. Wait at least 15 minutes before replacing your contact lenses. If you wear soft contact lenses, your doctor may direct you not TO wear them until your levocabastine treatment is finish. Check with your doctor before you begin using them again. TO apply levocabastine, shake bottle before each USE. Tilt your head back, look upward, and pull down the lower eyelid TO make a pouch. Hold dropper directly over your eye and place one drop into pouch as directed by your doctor. Look downward, gently close your eyes, and place one finger at the corner of your eye. Apply gentle pressure for 1 TO 2 minutes before opening your eyes. This will prevent medication from draining out. Try not to blink or rub your eye. Repeat these steps if your dose is for more than one drop. If direct TO USE this medication in both eyes, repeat these steps for your other eye. Do not rinse dropper. Replace dropper cap after each USE. Dosage is based on your medical condition and response TO treatment. Apply as often as directed by your doctor, usually 1 drop in each eye twice a day. Your doctor may direct you TO USE this medication as often as 3 TO 4 times a day. Follow your doctor's directions carefully. USE this medication regularly TO get the most benefit from it. TO help you remember, USE it at same time each day. Do not USE this bottle more than 1 month after first opening it or if it becomes contaminate. The USE of contaminated eye medication can cause infection, serious damage to the eye, and loss of vision. Tell your doctor if your symptoms persist or worsen after 3 days.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

PRECAUTIONS

Levocabastine was not carcinogenic in male or female rats or in male mice when administered on diet for up to 24 months. In female mice, levocabastine doses of 5 000 and 21 500 times the maximum recommended ocular human use level result in increased incidence of pituitary gland adenoma and mammary gland adenocarcinoma possibly produced by increased prolactin levels. The clinical relevance of this finding is unknown with regard to interspecies differences in prolactin physiology and very low plasma concentrations of levocabastine following ocular administration. Mutagenic potential was not demonstrated for levocabastine when tested in Ames' Salmonella reversion test or in Escherichia coli, Drosophila melanogaster, mouse Dominant Lethal Assay or in rat Micronucleus test. In reproduction studies in rats, levocabastine showed no effects on fertility at oral doses of 20 mg / kg / day.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

What is this medicine?

There are no published reports of excretion of levocabastine into breastmilk. The manufacturer reports that levocabastine was found in the breast milk of one nursing woman after ophthalmic administration of the drug. The daily dosage of levocabastine that infant would receive was calculated to be about 0. 5 mcg. Infant Levels. Relevant published information has not been found as of revision date. Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether effects on prolactin have any consequences on breastfeeding success has not been study. Prolactin level in a mother with established lactation may not affect her ability to breastfeed.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

NTS1 Receptors

Autoradiographic studies using NT in presence of blocking concentrations of levocabastine have revealed selective association of NTS1-binding sites with selective neuronal populations throughout the hypothalamus, basal forebrain, and limbic system. High concentrations of NTS1-binding sites were distributed in perikarya and dendrites of subsets of chemospecific neurons in a variety of brain regions, including DA neurons in ventral midbrain, cholinergic neurons in basal forebrain, and vasoactive intestinal peptidergic neurons in the suprachiasmatic nucleus of the hypothalamus. This distribution is consistent with the report NTS1-mediate NT effects on locomotion, memory, cognition, circadian rhythms, and sleep-waking cycle, as well as on regulation of hypothalamopituitary functions. Accordingly, all these regions were later found to contain numerous nerve cell bodies expressing NTS1 mRNA and / or NTS1 receptor proteins by in situ hybridization and immunohistochemistry, respectively. Highest levels of staining were observed on the islands of Calleja, diagonal band of Broca, magnocellular preoptic nucleus, pre-and parasubiculum, suprachiasmatic nucleus, anterodorsal nucleus of thalamus, substantia nigra, and VTA. At the cellular level, NTS1 receptors were predominantly associated with perikarya and dendrites in some regions and with axons and axon terminals in others. These labeling patterns suggest that neurons expressing NTS1 receptors target these receptors to both their somatodendritic and axonal elements, providing evidence for pre-and postsynaptic effects of NT in different brain regions. At the subcellular level, in all areas examine, significant proportion of both immunoreactive and radiolabeled NTS1 was found in association with neuronal plasma membranes. In brief, in nucleus accumbens, NTS1 receptors were mainly associated with the plasma membrane of axon terminals, whereas they were mostly observed over the membrane of DA neurons in substantia nigra and VTA. By contrast, dendrites show higher concentration of intracellular receptors, suggesting that neurons expressing NTS1 receptors maintain large receptor reserves. Important fractions of these intracellular receptors are associated with Golgi apparatus and endoplasmic reticulum, indicating that newly synthesize receptor proteins are in the process of synthesis and posttranslational modifications. Electron microscopy immunocytochemistry also revealed NTS1 receptors in endosomal vesicles, suggesting that NTS1 receptors internalize on ligand stimulation. Autoradiographic studies using NT in presence of blocking concentrations of levocabastine have revealed selective association of NTS1-binding sites with selective neuronal populations throughout the hypothalamus, basal forebrain and limbic system. High concentrations of NTS1-binding sites were distributed in perikarya and dendrites of subsets of chemo-specific neurons in a variety of brain regions, including DA neurons in ventral midbrain, cholinergic neurons in basal forebrain and vasoactive intestinal peptidergic neurons in the supra chiasmatic nucleus of the hypothalamus. This distribution is consistent with the report NTS1-mediate NT effects on locomotion, memory, cognition, circadian rhythms and sleep-waking cycle, as well as on regulation of hypothalamo-pituitary functions. Accordingly, all these regions were later found to contain numerous nerve cell bodies expressing NTS1 mRNA and / or NTS1 receptor proteins by in situ hybridization and immunohistochemistry, respectively.


General

Tridecapeptide neurotensin mediate its central and peripheral effects through interaction with three identified receptor subtypes, referred to as NTS 1, NTS 2 and NTS 3. NTS 1 and NTS 2 belong to 7 transmembrane domain / GPCR family, whereas Sortilin 1 is a single transmembrane domain receptor. Therefore, following introduction summarise only the properties of two GPCRs NTS 1 and NTS 2.


Neurotensin

NTR2 is a low-affinity receptor that shares about 60 % homology with NTR1 and is sensitive to levocabastine. Although it has characteristics of G protein-couple receptor, transduction mechanisms have not been completely characterized and appear to be system and species specific. Furthermore, neurotensin antagonists have paradoxical agonist functions in some species. The Receptor is expressed mostly in the brain but in a distribution pattern different to NTR1, so there is rarely coexpression. NTR2 receptor appear to mediate neurotensin-induced analgesia. No specific gastrointestinal role has been demonstrated for NTR2 and no NTR2 binding sites could be detected in human colons and no NTR2 mRNA in human pancreatic and colon cancer cell lines.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

NTS2 Receptors

The NTS2 receptor is also a G-protein-couple receptor with seven transmembrane domains. This receptor, in contrast to NTS1, is a low-affinity receptor that can be blocked by levocabastine and is relatively insensitive to Na + ions and GTP. Replacement of Asp by Ala or Gly in the second transmembrane domain is believed to be responsible for decreased affinity of receptor. This receptor has been localized mostly in the brain. It is specifically expressed in the olfactory system, cerebral and cerebellar cortices, hippocampal formation, and certain hypothalamic nuclei. The NTS2 receptor is implicated in NT-induced analgesia. For example, intracerebroventricular injection of antisense oligonucleotides, which specifically block NTS2 expression, inhibits NT-induced analgesia. These oligonucleotides have NO effect on other receptors. Furthermore, SR48692, which does not block NTS2, also does not inhibit NT analgesia.


Results

To explore whether NOS activity changes involve alteration in enzyme expression, western blot assays were carried out. In each experiment, membrane samples isolated from tissue of levocabastineinjected rats were run in parallel with samples isolated from control tissue. Figures 4 and 5 show immunoblots from single representative experiments for cerebral cortex synaptosomal membranes and mitochondria. Figures 4 and 5 show quantitative data from 3 to 6 assays carried out with paired samples. Levocabastine administration decreases expression of tubuline and actine. Therefore, data for nNOS optical density of synaptosomal membrane fractions from control and levocabastinetreated rats were express relativizing values to control group. As shown in Fig 4, nNOS expression in synaptosomal membranes decreased by 18 and 56 % after 30 min and 18 h of levocabastine treatment, respectively. An increasing trend in NOS expression was observed in purified mitochondria 30 min after levocabastine administration, whereas 86 % enhancement in protein enzyme expression was observed 18 h after drug administration.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

NTS3 Receptors

The Existence of two distinct receptor sites for NT has been evidence by ligand binding studies on rat brain synaptic membranes: high affinity NT binding site, later clone as NTS 1 receptor, and lower affinity NT binding site, NTS 2 receptor. NTS 1 was the first clone from rat brain by Tanaka et al. Human NTS 1 was clone from colonic adenocarcinoma cell line HT29 and shares 84 % homology with rat NTS 1 receptor. NT binds to these NTS 1 receptors with an affinity of 0. 1-0. 4 nM, in comparison with 2-5 nM for NTS 2. With regard to G protein-coupling, NTS 1 is G q-preferring receptor since in almost all systems examine binding of NT to NTS 1 activated phospholipase C. However, coupling of NTS 1 to G I / O and to G S has been observed in some expression systems. Activation of NTS 1 is probably responsible for observed effects of NT on cancer cell proliferation and food intake. However, most convincing implication of NTS 1 is related to NT-dopamine interactions in the brain. Indeed, NT modulates dopamine transmisssion in nigro-striatal and mesocorticolimbic pathways through NTS 1, indicating that NT analogues specifically targeting this receptor might represent a new class of antipsychotic drugs. NTS 2 was clone from mouse and rat brain with use of NTS 1 homology screening protocol. Human NTS 2 was further clone and is 82 % identical to rat and mouse counterparts. Pharmacologically, mouse and rat NTS 2 can be easily distinguished from other NT receptors by levocabastine, histamine H 1 antagonist, which totally and selectively inhibits binding of NT to NTS 2. Signal transduction of NTS 2 is unclear because it depends on the cell system of expression use and on receptor species. For example, NT activates mouse NTS 2 when expressed in oocytes but is unable to activate the same receptor expressed in HEK cells. Rat NTS 2 has been shown to be involved in NT-induced Erk1 / 2 phosphorylation by a mechanism that is dependent on receptor internalisation. In contrast, human NTS 2 can increase cytosolic calcium only when activated by selective NTS 1 antagonist SR48692, and NT has been shown to inhibit this effect as an antagonist. Difficulty in studying the signal transduction mechanism of NTS 2 certainly comes from its ability to be constitutively active. NTS 2 contributes to the protective effect of NT on pancreatic beta cells. NTS 2 has been described to be responsible for analgesic response of centrally administered NT. This observation is enhanced by cerebral localisation of both its messenger RNA and its protein in structures implicated in descending control of nociceptive imputs, especially in periaqueductal gray and dorsal raphe. However, expression of NTS 2 immunoreactivity in areas devoid of neurotensinergic inputs indicate that NT might not be an exclusive endogenous ligand for NTS 2.


General

Tridecapeptide neurotensin mediate its central and peripheral effects through interaction with three identified receptor subtypes, referred to as NTS 1, NTS 2 and NTS 3. NTS 1 and NTS 2 belong to 7 transmembrane domain / GPCR family, whereas Sortilin 1 is a single transmembrane domain receptor. Therefore, following introduction summarise only the properties of two GPCRs NTS 1 and NTS 2.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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