Serotonin–norepinephrine reuptake inhibitor - Wikiwand
Selegiline (a drug used in Parkinson disease) is metabolized to . ACE inhibitors reduce vasoconstriction and aldosterone activity by blocking the enzyme Ecarin based assays have shown utility in correlation with dabigatran as well. Based on its structural similarity to tricyclic antidepressants, carbamazepine may . OXcarbazepine Oral (Drug Facts And Comparisons) Full search results .. Dosage: Hepatic function impairment Structural similarity of oxcarbazepine to carbamazepine, available clinical evidence, and data from nonclinical studies showing a direct . OXcarbazepine may enhance the serotonergic effect of Selegiline. The crystalline structure of five enantiomeric hydrochlorides were which are known to be the active metabolites of the antiepileptic drug oxcarbazepine (OXC) . . Finally, we performed rescue expriments to confirm the function relationship.
It may even be that common side effects of serotonergic medications actually represent a milder form of acute serotonin syndrome. In addition to the acute severe syndrome of serotonin excess, there are motor side effects of the SSRIs very similar to the extrapyramidal side effects EPS associated with neuroleptics, including lasting dyskinesias and perhaps even tardive dyskinesia.
The existence of SSRI-induced EPS and the clinical similarity between serotonin syndrome and neuroleptic malignant syndrome NMSassociated with acute dopaminergic blockade, suggests that the balance between serotonergic and dopaminergic systems in the brain may be more important than an excess or deficiency of one of the neurotransmitters in the pathophysiology of these disorders.
Finally, there is a concern that the long-term suppression of the CYP2D6 system may increase the risk for developing Parkinson's disease and tardive dyskinesia by blocking the metabolism of certain neurotoxins that destroy the dopaminergic nigrostriatal tract. Clearly, given the potentially life-threatening nature of serotonin syndrome and the possibility of long-term complications from treatment with drugs that manipulate the serotonergic system, it is imperative to take a cautious approach to prescribing these drugs, for example, having clear target symptoms in mind before prescribing, ensuring adequate washout periods between drugs, and carefully monitoring motor side effects in the same way as one does with the neuroleptics e.
Overview of Serotonin System In order to understand the symptoms, pathophysiology, and triggers for serotonin syndrome and SSRI-induced EPS, it is necessary to understand the anatomy and physiology of the serotonin system. Briefly, activities of serotonin in the peripheral nervous system include vasoconstriction via smooth muscle stimulation, platelet aggregation, uterine contraction, intestinal peristalsis, and bronchoconstriction. Serotonin in the central nervous system has effects on controlled behavior, attention, affect, cardiorespiratory function, pain perception, aggression, motor control, temperature, sleep, appetite, and sexual function.
As serotonin is unable to cross the blood—brain barrier, it must be produced both centrally and peripherally. Platelets utilize an uptake pump to scavenge serotonin produced by the intestinal enterochromaffin cells, the only peripheral source of serotonin.
The brainstem raphe nuclei consist of nine nuclei that produce serotonin, forming an inferior caudal group, which sends excitatory axons to the spinal cord and medulla descending pathwaysand a superior rostral group, from which ascending projections ascending pathways inhibit thalamic and cortical regions . It has been postulated that ascending pathways are associated with sleep and synchronization of cortical neurons, whereas descending antinociceptive-type pathways, when stimulated, result in inhibition of neurons in the spinothalamic tract and cause analgesia.
It is estimated that, in human body, there is about 10 mg of serotonin present, most of which 4—8 mg is found in enterochromaffin cells located in gastric and intestinal mucosa. The rest is in platelets serotonin is not synthesized in platelets although it is taken up from plasma and stored in platelets and in the CNS.
Serotonin is generally found to be complexed with ATP and divalent cations in serotonin-containing cells. The synthesis of serotonin begins when ingested tryptophan crosses the blood—brain barrier via a nonspecific amino acid transporter and enters neurons to be hydrolyzed the rate-limiting step and subsequently decarboxylized to serotonin, resulting in placement into storage vesicles ready for release into the synaptic cleft with depolarization of the presynaptic neuron .
There are presynaptic and postsynaptic receptors, the stimulation of the former turning off the further release of serotonin and the latter, with summation at the hillock, affecting depolarization of the axons that run to terminal fields in the cortex, thalamus, medulla, and spinal cord.
Serotonin is removed from the cleft via reuptake pumps and is either repackaged into storage vesicles or degraded by monoamine oxidase MAOwhich is present on the mitochondrial membrane, into 5-hydroxy indole acetic acid 5-HIAA. There are two isoforms of MAO: The serotonin system has the largest number of receptors and subtypes of any of the neurotransmitter systems.
Finally, the GI tract is rich in 5-HT4 receptors, which modify peristalsis. Whether it is direct or indirect, excess stimulation of postsynaptic, especially 5-HT1A and 5-HT2, receptors appears necessary to produce serotonin syndrome. Therefore, the key point in the management of serotonin syndrome is the identification and discontinuation of the causative agents. Serotonin Syndrome Clinical Characteristics and Diagnosis Serotonin syndrome, the most acute manifestation of excess serotonin at the synapse, usually consists of a triad of symptoms including cognitive- behavioral changes, neuromuscular excitability, and autonomic instability, although only one category of symptoms may predominate.
The diagnosis is made on clinical grounds alone, and there is a broad range in both the severity of presentation and the constellation of symptoms observed, and hence mild, atypical cases are very likely to be missed or mistaken for worsening psychiatric or neurological illnesses.
The most current diagnostic criteria require three of the following: Agitation, mental status changes confusion, hypomaniamyoclonus, shivering, tremor, hyperreflexia, ataxia, diarrhea or fever .
In addition, a recent increase in dosage or addition of known serotonergic agents to an established medication regimen, with no recent change in dosage or addition of a dopaminergic agent, must be present, and of course, other possible etiologies, for example, infection, metabolic disorder, or substance intoxication or withdrawal, need to be ruled out before a diagnosis of serotonergic syndrome can be made.
Other symptoms, although not required for diagnosis, can include: Diaphoresis, trismus, parasthesias, incoordination, and head twitching. Autonomic instability involving diaphoresis, mild elevations in temperature, hypertension, and tachycardia is commonly seen. Less often, hypotension can occur.
Although patients often hyperventilate and appear flushed on presentation, in severe cases, muscular rigidity can lead to progressive hypoventilation with ensuing cyanosis. Lab tests are not useful for the diagnosis of serotonin syndrome.
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Urinary 5-HIAA has too long of a laboratory turnover time, and drug levels are often within the therapeutic range. Additionally, cerebrospinal fluid studies, computerized tomography scans, electrolytes, and liver enzymes are unremarkable. Occasionally, abnormal lab findings can include mildly elevated muscle creatine kinase levels in correlation with the degree of muscle rigidity, a mild elevation in liver enzymes with associated hyperammonemia, abnormally low or high white blood cell counts, and EEG findings of diffuse slowing consistent with a diffuse metabolic encephalopathy.
The differential diagnosis usually includes neuromuscular malignant syndrome NMSsepsis with meningitis, delirium tremens, anticholinergic toxicity, heat stroke, and sympathomimetic overdose.
Historical and lab data are crucial to rule out these other disorders. Fluorescent polystyrene nanoparticle used for initial targeting studies. Targeted form includes a rho end group.
Untargeted control contains a CH3 end group. Schematic diagram of a circular parallel-plate flow chamber. Cells are grown on a glass surface over which a gasket is placed allowing the flow of reagents over the top of the cells. Attachment of beads to the cell surface is quantified by use of a fluorescent microscope positioned above the flow chamber visible window. Flow chamber data from flow chamber studies. The results show that control beads without rhodamine do not adhere to either P-gp expressing or P-gp expressing MCF-7 cells, whereas beads containing rhodaminel23 adhere to P-gp expressing MCF-7 cells, but not to non-expressing cells.
Synthesis of mPEG-Rho by nucleophilic attack at the 2' position. Stejskals-Tanner plots of diffusion ordered NMR. Covalent attachment evident from equal diffusion of Rho peaks and mPEG peaks. Both mPEG- Rhol23 conjugate and free Rhol23 showed an increase in accumulation ratio with increasing verapamil concentration. All bars are an average of 3 replicates. Scale bar is nm. Initial biodistribution data using europium nanospheres. Europium was able to be detected against background tissue fluorescence.
Error bars are representative of standard deviations. After the delivery vehicle is administered to a mammalian subject i. In both sets of embodiments, the drug can be released locally. The delivery system of this invention is particularly useful for delivery of compounds to tissues and cells expressing high levels of P-gp, such as multi drug resistant cancerous cells, blood brain barrier, and gastrointestinal epithelium, for therapeutic treatment of cancer, CNS disorders and GI disorders, among others.
The P-gp targeting composition can be conveniently depicted by the following general structure: The bonds are independently of any type that can be maintained i. Thus, the first and second bonds should be of sufficient strength, such as, independently, a covalent, ionic, or affinity bond. For example, although Formula 1 depicts a single drug-loaded carrier, Formula 1 includes the possibility of a multiplicity e.
In the case of multiple drug-loaded carriers, the straight line representing the first bond can represent multiple bonds. Similarly, the linker provided in Formula 1 may represent a single linker or a multiplicity of linkers, and the P-gp substrate provided in Formula 1 may represent a single P-gp substrate or a multiplicity of P-gp substrates.
In the case of multiple P-gp substrates, the straight line representing the second bond can represent multiple bonds. The term "biocompatible", as used herein, refers to the characteristic of certain substances to not induce a substantially adverse physiological response e.
Thus, a determination of biocompatibility is distinct from determining side effects, since side effects are generally an accepted aspect of any drug. In some embodiments, the term "biocompatible" indicates that the composition or a component thereof fails to elicit any detectable immunological or toxicological response from the subject being administered the composition.
The biocompatible framework can have any structure suitable for carrying a drug. The drug can be carried i. In the foregoing embodiment, the drug can reside in the hollow interior portion, in which case the surrounding biocompatible material encapsulates the drug.
If the encapsulating material is porous, the pores may be nanoporous, mesoporous, or macroporous, or a combination thereof, as long as the pores are small enough to maintain a substantial portion e.
Once docked at the P-gp site, the pores may serve to slowly release the drug. The framework in which the drug can intercalate may or may not include a hollow interior portion.
Thus, in some embodiments, the drug may be encapsulated while also being intercalated in another portion of the biocompatible framework. Such intercalating structures for drug delivery are well known in the art. The encapsulating polymer can be, for example, a polyhydroxyacid biopolyester, polysaccharide, polyacrylate, polymethacrylate, polyalkyleneglycol, polyphosphazene, polyanhydride, polyacetal, poly ortho esterspolyurea, polyurethane, polyamide, poly amino acidpolyphosphoester, or a co-polymer thereof.
Other polymer chemistries are possible, such as polycarbonates, polypyrroles, polyoxazoline, and polysiloxanes. A comprehensive review of these and other biocompatible polymers and their use in drug delivery is provided in G. Two particular subclasses of biopolyesters considered herein are the poly cc-hydroxy acid s and poly hydroxyalkanoates.
Any biocompatible and suitably hydrophilic homopolymer or copolymer containing a polymerized block of any one, two, or more of these cc-hydroxy acids are considered herein. A copolymer containing one or more poly cc-hydroxy acid blocks may also include one or more non-cc-hydroxy acid polymer blocks, such as one or more polyalkyleneglycol blocks e.
Such polymers and copolymers are well known in the art, as evidenced by, for example, F. Control Release, Nov 9;77 l Any biocompatible and suitably hydrophilic homopolymer or copolymer containing a polymerized block of any one, two, or more of these hydroxyalkanoic acids are considered herein. Some examples of poly hydroxyalkanoates include poly 3-hydroxypropionatepoly 3-hydroxybutyratepoly 4-hydroxybutyratepoly 3-hydroxyvaleratepoly 4-hydroxyvaleratepoly 5- hydroxy valeratepoly s-caprolactonepoly 3-hydroxyhexanoateand poly 3- hydroxyoctanoateas well as co-polymers thereof, such as a copolymer of 3-hydroxybutyrate and 3 -hydroxy valerate i.
A copolymer containing one or more poly hydroxyalkanoate blocks may also include one or more non-hydroxyalkanoate polymer blocks, such as one or more polyalkyleneglycol blocks e. Such polymers and copolymers are well known in the art, as evidenced by, for example, U. Perspective", International Journal of Microbiologyvol. The polysaccharide may be based on, for example, dextran, dextran sulfate, hyaluronic acid, alginate, heparin, chondroitin sulfate, pectin, pullulan, amylose, a cyclodextrin, a chitosan e.
Such polymers and their use in drug delivery are well known in the art, as evidenced by, for example, Z. Some examples of such polymers include polyacrylic acid, polyacrylate salt, polymethacrylic acid, polymethacrylate salt, poly methyl acrylatepoly methyl acrylatepoly ethyl acrylatepoly methyl methacrylatepoly 2-hydroxyethyl acrylatepoly 2-hydroxyethyl methacrylatepolyvinyl alcohol, polyvinyl acetate, and polyacrylamides, including N- substituted versions thereof, such as poly N-isopropylacrylamideas well as combinations and co-polymers thereof.
Such polymers and their use in drug delivery are well known in the art, as evidenced by, for example, Garay- Jimenez, J. The polyalkylene glycol can be any of the polyalkylene glycols known in the art, such as polyethylene glycol, polypropylene glycol, or poly trimethylene glycolor a combination or co-polymer thereof.
Such polymers and their use in drug delivery are well known in the art, as evidenced by, for example, K. Effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles", Colloid and Polymer Science, As known in the art, polyphosphazenes are polymers that possess an inorganic backbone constructed of alternating phosphorus and nitrogen atoms, with variable side chains attached to the phosphorus atoms.
The polyphosphazenes have the particular advantage of synthetic flexibility, ease of fabrication, and matrix permeability. Such polymers and their use in drug delivery are well known in the art, as evidenced by, for example, S.
Such polymers and their use in drug delivery are well known in the art, as evidenced by, for example, C. Polyacetal polymers and their use in drug delivery are well known in the art, as evidenced by, for example, J. Poly ortho ester polymers and their use in drug delivery are well known in the art, as evidenced by, for example, U. Polyurea polymers and their use in drug delivery are well known in the art, as evidenced by, for example, U.
Morral- Ruiz, et al. Polyamide polymers and their use in drug delivery are well known in the art, as evidenced by, for example, U. Patent 8, "Polyamide rate-modulated monolithic drug delivery system" ; I.
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Polyurethane polymers and their use in drug delivery are well known in the art, as evidenced by, for example, U. Film characterization and preliminary in vivo study", Macromolecular Research, vol. The poly amino acid can be derived from any known natural or unnatural amino acid. Some examples of poly amino acids include poly-y-glutamic acid, polyaspartic acid, polyserine, polythreonine, polylysine, polyglutamine, polyasparagine, polyarginine, and polycysteine, as well as copolymers thereof.
Poly amino acid polymers and their use in drug delivery are well known in the art, as evidenced by, for example, A. Lalatsa, "Amphiphilic poly L-amino acids - new materials for drug delivery", J. Control Release, 2, pp. A, 8Aug. Polyphosphoester polymers and their use in drug delivery are well known in the art, as evidenced by, for example, Z.
As well known in the art, a liposome has a lipid bilayer structure formed by the ordered assembly of amphiphilic molecules. In an aqueous environment, the liposome possesses a hydrophobic layer having inner and outer surfaces that are hydrophilic. Thus, if the drug is suitably hydrophilic, the drug may be encapsulated in an interior portion of the liposome or be attached to an outer surface thereof, whereas, if the drug is suitably hydrophobic, the drug may be intercalated within the hydrophobic layer of the liposome.
The liposome can have any of the compositions well known in the art, such as a phosphatidylcholine phospholipid composition, phosphatidylethanolamine phospholipid composition, phosphatidylinositol phospholipid composition, or phosphatidylserine phospholipid composition. Liposome compositions and their use in drug delivery are well known in the art, as evidenced by, for example, U. B, ; all of which are herein incorporated by reference in their entirety.
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As well known in the art, a micelle is distinct from a liposome in that it is not a bilayer structure and possesses a hydrophobic interior formed by the ordered interaction of amphiphilic molecules. Thus, a drug of sufficient hydrophobicity may be intercalated or encapsulated within the micellular structure, while a drug of sufficient hydrophilicity may be attached to the outer surface of the micelle.
Micellular compositions and their use in drug delivery are well known in the art, as evidenced by, for example, U.
Control Release, Nov 9;77 1- 2: The dendrimer can be any of the dendrimers known in the art that can suitably carry a drug in a biological system, such as the well-known poly amidoamine PAMAM dendrimers, amino acid-based dendrimers, ester-containing biodegradable dendrimers, and glycodendrimers.
Dendrimer compositions and their use in drug delivery are well known in the art, as evidenced by, for example, M.