DOCSLIB.ORG

Tepzz 96 ¥99B T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tepzz 96 ¥99B T (19) TZZ _¥_T (11) EP 2 961 399 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/19 (2006.01) A61K 31/196 (2006.01) 15.11.2017 Bulletin 2017/46 A61P 11/00 (2006.01) A61P 25/20 (2006.01) A61P 43/00 (2006.01) A61K 31/20 (2006.01) (2006.01) (2006.01) (21) Application number: 14709858.6 A61K 31/33 A61K 31/505 A61K 31/55 (2006.01) A61K 31/616 (2006.01) (22) Date of filing: 28.02.2014 (86) International application number: PCT/US2014/019217 (87) International publication number: WO 2014/134380 (04.09.2014 Gazette 2014/36) (54) ADMINISTRATION OF GAMMA HYDROXYBUTYRATE WITH MONOCARBOXYLATE TRANSPORTERS VERABREICHUNG VON GAMMA-HYDROXYBUTYRAT MIT MONOCARBOXYLAT-TRANSPORTERN ADMINISTRATION D’ACIDE 4-HYDROXYBUTANOÏQUE ET DE TRANSPORTEURS MONOCARBOXYLATE (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Fuller D ET AL: "From Club Drug to Orphan Drug: GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Sodium Oxybate (Xyrem) for the Treatment of PL PT RO RS SE SI SK SM TR Cataplexy", , 1 September 2003 (2003-09-01), XP055123175, Retrieved from the Internet: (30) Priority: 01.03.2013 US 201361771557 P URL:http://onlinelibrary.wiley.com/store/1 12.03.2013 US 201361777873 P 0.1592/phco.23.10.1205.32756/asset/phco.23 .10 15.03.2013 US 201313837714 .1205.32756.pdf?v=1&t=hwd6sj5s&s=83f56b 29.04.2013 US 201313873000 e5dea98a39c083d39d2396ab75a192f4ac 29.04.2013 US 201313872997 [retrieved on 2014-06-13] • Viviane Hechler ET AL: (43) Date of publication of application: "gamma-Hydroxybutyrate Conversion into 06.01.2016 Bulletin 2016/01 GABA Induces Displacement of GABA B Binding that is Blocked by Valproate and Ethosuximide (73) Proprietor: Jazz Pharmaceuticals Ireland Limited 1", , 30 January 1997 (1997-01-30), XP055123267, Dublin 4 (IE) Retrieved from the Internet: URL:http://jpet.aspetjournals.org/content/ (72) Inventor: ELLER, Mark 281/2/753.full.pdf#page=1&view=FitH [retrieved Redwood City, CA 94061 (US) on 2014-06-13] • BHATTACHARYA I ET AL: "GHB (74) Representative: Jones Day (GAMMA-HYDROXYBUTYRATE) Rechtsanwälte,Attorneys-at-Law, Patentanwälte CARRIER-MEDIATED TRANSPORT ACROSS Prinzregentenstrasse 11 THE BLOOD-BRAIN BARRIER", JOURNAL OF 80538 München (DE) PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, US, vol. 311, no. 1, 1 October 2004 (2004-10-01), pages 92-98, XP009049440, ISSN: 0022-3565, DOI: 10.1124/JPET.104.069682 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 961 399 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 961 399 B1 • PETRINE WELLENDORPH ET AL: "Phenylacetic acids and the structurally related non-steroidal anti-inflammatory drug diclofenac bind to specific [gamma]-hydroxybutyric acid sites in rat brain", FUNDAMENTAL & CLINICAL PHARMACOLOGY, vol. 23, no. 2, 1 April 2009 (2009-04-01), pages207-213, XP055123069, ISSN: 0767-3981, DOI: 10.1111/j.1472-8206.2008.00664.x 2 1 EP 2 961 399 B1 2 Description (Mg•(GHB)2), and a calcium salt of gamma-hydroxybu- tyrate (Ca•(GHB)2). 1. CROSS REFERENCE [0011] The methods of treatment disclosed herein are to be construed as referring to the compounds of the [0001] This application claims priority from U.S. Provi- 5 invention for use in those methods. sional Application No. 61/771,557, filed March 1, 2013, [0012] Herein disclosed is a method for treating a pa- and U.S. Provisional Application No. 61/777,873, filed tient who is suffering from excessive daytime sleepiness, March 12, 2013. cataplexy, sleep paralysis, apnea, narcolepsy sleep time disturbances, hypnagogic hallucinations, sleep arousal, 2. BACKGROUND 10 insomnia, and nocturnal myoclonus with gamma-hy- droxybutyrate (GHB) or a salt thereof, comprising: orally [0002] This application relates to methods for safely administering to the patient in need of treatment, an ad- administering gamma hydroxybutyrate (GHB) together justed dosage amount of the salt of GHB when the patient with one or more other monocarboxylate transporter is receiving a concomitant administration of valproate. In (MCT) inhibitors for therapeutic purposes. Example15 certain cases the adjusted amount is reduced at least transporter inhibitors are valproate, diclofenac, and ibu- about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, profen and combinations thereof. Fuller et al., "From Club 45%, or 50% of the normal dose of the salt of GHB nor- Drug to Orphan Drug: Sodium Oxibate (Xyrem) for the mally given to the patient. In certain cases the amount treatment of Cataplexy," Pharmacotherapy,of GHB is reduced at least about 10% and about 30% of 23(9):1205-9, 2003 discloses the use gamma-hydroxy- 20 the normal administration and the daily administration of butyrate to treat cataplexy in patients with narcolepsy. the GHB salt is between 1 gram and 10 grams. In certain cases the adjusted amount is reduced between the rang- 3. SUMMARY OF THE INVENTION es of about 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% [0003] In one aspect, the invention provides gamma- 25 to 30%, about 30% to 35%, about 35% to 40%, about hydroxybutyrate (GHB) or a salt thereof for use in a meth- 40% to 45%, or about 45% or 50%, relative to the normal od of treating narcolepsy in a patient, wherein said patient dose of the salt of GHB normally given to the patient. In is also taking or will be taking divalproex sodium, the certain cases the adjusted amount is reduced between method comprising administering GHB or a salt thereof the range of about 1% to 50%, about 1% to 45%, about to the patient in a dose that is reduced by 10% to 40% 30 1% to 40%, about 1% to 35%, about 1% to 30%, about to compensate for the effect caused by the divalproex 1% to 25%, about 1% to 20%, about 1% to 15%, about sodium, wherein the dose of GHB or salt thereof when 1% to 10%, about 1% to 5%, about 5% to 50%, about the patient is not taking the divalproex sodium is between 5% to 45%, about 5% to 40%, about 5% to 35%, about 4.5 g to 9.0 g/day. 5% to 30%, about 5% to 25%, about 5% to 20%, about [0004] In one embodiment, the GHB or salt thereof is 35 5% to 15%, about 5% to 10%, about 10% to 50%, about administered in a dose that is reduced by 15% to 25% 10% to 45%, about 10% to 40%, about 10% to 35%, to compensate for the effect caused by the divalproex about 10% to 30%, about 10% to 25%, about 10% to sodium. 20%, about 10% to 15%, about 15% to 50%, about 15% [0005] In a further embodiment the GHB or salt thereof to 45%, about 15% to 40%, about 15% to 35%, about is administered in a dose that is reduced by 20% to com- 40 15% to 30%, about 15% to 25%, about 15% to 20%, pensate for the effect caused by the divalproex sodium. about 15% to 15%, about 15% to 10%, about 20% to [0006] In certain embodiments, the GHB or salt thereof 50%, about 20% to 45%, about 20% to 40%, about 20% is prepared as a formulation which has a concentration to 35%, about 20% to 30%, about 20% to 25%, about of between 350 - 750 mg/ml. 25% to 50%, about 25% to 45%, about 25% to 40%, [0007] In further embodiments, the GHB or salt thereof 45 about 25% to 35%, about 25% to 30%, about 30% to is prepared as a formulation which has a concentration 50%, about 30% to 45%, about 30% to 40%, about 30% of between 450 - 550 mg/ml. to 35%, about 35% to 50%, about 35% to 45%, about [0008] In another embodiment, the GHB or salt thereof 35% to 40%, about 40% to 50%, relative to the normal is prepared as a formulation which has a pH between 6 dose of the salt of GHB normally given to the patient. - 10. 50 [0013] Further disclosed herein is a method of safely [0009] In a further embodiment, the GHB or salt thereof administering GHB a salt thereof for excessive daytime is prepared as a formulation which has a pH between 6.5 sleepiness, cataplexy, sleep paralysis, apnea, narcolep- - 8. sy, sleep time disturbances, hypnagogic hallucinations, [0010] In yet another embodiment, the salt comprises sleep arousal, insomnia, and nocturnal myoclonus in a a single salt or a mixture of salts of GHB selected from 55 human patient, comprising: determining if the patient is a sodium salt of gamma-hydroxybutyrate (Na•GHB), a has taken, or will take a concomitant dose of valproate; potassium salt of gamma-hydroxybutyrate (K•GHB), a orally administering a reduced amount of the GHB or magnesium salt of gamma-hydroxybutyrateGHB salt to the patient compared to the normal dose so 3 3 EP 2 961 399 B1 4 as to diminish the additive effects of the GHB or GHB sleep arousal, insomnia, and nocturnal myoclonus in a salt when administered with valproate.
Load more

Recommended publications
  • Summary: Traditionally, Bioanalytical Laboratories Do Not Report Actual
    Summary: Traditionally, bioanalytical laboratories do not report actual concentrations for samples with results below the limit of quantification (BLQ) in pharmacokinetic studies. BLQ values are outside the method calibration range established during validation and no data are available to support the reliability of these values. However, ignoring BLQ data can contribute to bias and imprecision in model-based pharmacokinetic analyses. From this perspective, routine use of BLQ data would be advantageous. We would like to initiate an interdisciplinary debate on this important topic by summarising the current concepts and use of BLQ data by regulators, pharmacometricians and bioanalysts. Through introducing the limit of detection and evaluating its variability BLQ data could be released and utilized appropriately for pharmacokinetic research. Keywords: Lower limit of quantification (LLOQ) Below limit of quantification (BLQ) result Limit of detection (LoD) Pharmacokinetic (PK) Pharmacodynamics (PD) Introduction Studying the effects of drugs remains central to both medical research and clinical practice. Two key branches of pharmacological analysis are (i) pharmacokinetics (PK), including drug absorption, distribution, metabolism and elimination, and (ii) pharmacodynamics (PD), exploring the effects of drugs on the living organism, including efficacy and toxicity. In PK studies the samples are collected in an effort to map the drug concentration over time in the patient. For samples collected many hours post-dose drug concentrations may be low, yet can still provide valuable information on pharmacokinetic parameters such as clearance [1,2]. Similarly, in the case of biomarker PD studies, concentrations that are too low to quantify with a particular bioanalytical method may still provide useful information. Bioanalytical laboratories define the lowest concentration that can be quantified accurately by a method as the lower limit of quantification (LLOQ).
    [Show full text]
  • Opposing Effects of Dehydroepiandrosterone And
    European Journal of Endocrinology (2000) 143 687±695 ISSN 0804-4643 EXPERIMENTAL STUDY Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells M O Canning, K Grotenhuis, H J de Wit and H A Drexhage Department of Immunology, Erasmus University Rotterdam, The Netherlands (Correspondence should be addressed to H A Drexhage, Lab Ee 838, Department of Immunology, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands; Email: [email protected]) Abstract Background: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development. Aim: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (1026 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development. Results: The continuous presence of DHEA (1026 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity).
    [Show full text]
  • Block of GABAA Receptor Ion Channel by Penicillin: Electrophysiological and Modeling Insights Toward the Mechanism
    Molecular and Cellular Neuroscience 63 (2014) 72–82 Contents lists available at ScienceDirect Molecular and Cellular Neuroscience journal homepage: www.elsevier.com/locate/ymcne Block of GABAA receptor ion channel by penicillin: Electrophysiological and modeling insights toward the mechanism Alexey V. Rossokhin ⁎, Irina N. Sharonova, Julia V. Bukanova, Sergey N. Kolbaev, Vladimir G. Skrebitsky Research Center of Neurology, Russian Academy of Medical Sciences, 105064 Moscow, Russia article info abstract Article history: GABAA receptors (GABAAR) mainly mediate fast inhibitory neurotransmission in the central nervous system. Dif- Received 5 June 2014 ferent classes of modulators target GABAAR properties. Penicillin G (PNG) belongs to the class of noncompetitive Revised 29 September 2014 antagonists blocking the open GABAAR and is a prototype of β-lactam antibiotics. In this study, we combined elec- Accepted 7 October 2014 trophysiological and modeling approaches to investigate the peculiarities of PNG blockade of GABA-activated Available online 8 October 2014 currents recorded from isolated rat Purkinje cells and to predict the PNG binding site. Whole-cell patch-сlamp Keywords: recording and fast application system was used in the electrophysiological experiments. PNG block developed after channel activation and increased with membrane depolarization suggesting that the ligand binds within GABAA receptor Penicillin the open channel pore. PNG blocked stationary component of GABA-activated currents in a concentration- Isolated neurons dependent manner with IC50 value of 1.12 mM at −70 mV. The termination of GABA and PNG co-application Patch clamp was followed by a transient tail current. Protection of the tail current from bicuculline block and dependence Molecular modeling of its kinetic parameters on agonist affinity suggest that PNG acts as a sequential open channel blocker that pre- Monte-Carlo energy minimization vents agonist dissociation while the channel remains blocked.
    [Show full text]
  • 5-HT2A/2C Receptor Modulation of Absence Seizures and Characterization of the GHB-Model
    5-HT2A/2C receptor modulation of absence seizures and characterization of the GHB-model A thesis submitted to Cardiff University for the degree of Doctor of Philosophy by Marcello Venzi (MSc) School of Biosciences, Cardiff University, October 2014 Chapter 1 Declaration and Statements This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD . Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………………… (candidate) Date ………………………… II Chapter 1 Summary Absence seizures (ASs) are non-convulsive epileptic events which are common in pediatric and juvenile epilepsies. They consist of EEG generalized spike-and-wave-discharges (SWDs) accompanied by an impairment of consciousness and are expressed within the thalamocortical network.
    [Show full text]
  • Penicillin Allergy Guidance Document
    Penicillin Allergy Guidance Document Key Points Background Careful evaluation of antibiotic allergy and prior tolerance history is essential to providing optimal treatment The true incidence of penicillin hypersensitivity amongst patients in the United States is less than 1% Alterations in antibiotic prescribing due to reported penicillin allergy has been shown to result in higher costs, increased risk of antibiotic resistance, and worse patient outcomes Cross-reactivity between truly penicillin allergic patients and later generation cephalosporins and/or carbapenems is rare Evaluation of Penicillin Allergy Obtain a detailed history of allergic reaction Classify the type and severity of the reaction paying particular attention to any IgE-mediated reactions (e.g., anaphylaxis, hives, angioedema, etc.) (Table 1) Evaluate prior tolerance of beta-lactam antibiotics utilizing patient interview or the electronic medical record Recommendations for Challenging Penicillin Allergic Patients See Figure 1 Follow-Up Document tolerance or intolerance in the patient’s allergy history Consider referring to allergy clinic for skin testing Created July 2017 by Macey Wolfe, PharmD; John Schoen, PharmD, BCPS; Scott Bergman, PharmD, BCPS; Sara May, MD; and Trevor Van Schooneveld, MD, FACP Disclaimer: This resource is intended for non-commercial educational and quality improvement purposes. Outside entities may utilize for these purposes, but must acknowledge the source. The guidance is intended to assist practitioners in managing a clinical situation but is not mandatory. The interprofessional group of authors have made considerable efforts to ensure the information upon which they are based is accurate and up to date. Any treatments have some inherent risk. Recommendations are meant to improve quality of patient care yet should not replace clinical judgment.
    [Show full text]
  • Case 2:14-Cv-05824-ES-JAD Document 1 Filed 09/18/14 Page 1 of 35 Pageid: 1
    Case 2:14-cv-05824-ES-JAD Document 1 Filed 09/18/14 Page 1 of 35 PageID: 1 Charles M. Lizza William C. Baton SAUL EWING LLP One Riverfront Plaza, Suite 1520 Newark, New Jersey 07102-5426 (973) 286-6700 [email protected] Attorneys for Plaintiff Jazz Pharmaceuticals, Inc. UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY JAZZ PHARMACEUTICALS, INC., Civil Action No. ____________________ Plaintiff, COMPLAINT FOR PATENT INFRINGEMENT v. PAR PHARMACEUTICAL, INC., (Filed Electronically) Defendant. Plaintiff Jazz Pharmaceuticals, Inc. (“Jazz Pharmaceuticals”), by its undersigned attorneys, for its Complaint against defendant Par Pharmaceutical, Inc. (“Par”), alleges as follows: Nature of the Action 1. This is an action for patent infringement under the patent laws of the United States, 35 U.S.C. §100, et seq., arising from Par’s filing of an Abbreviated New Drug Application (“ANDA”) with the United States Food and Drug Administration (“FDA”) seeking ® approval to commercially market a generic version of Jazz Pharmaceuticals’ XYREM drug product prior to the expiration of United States Patent No. 8,772,306 (“the ’306 patent” or “the patent-in-suit”) owned by Jazz Pharmaceuticals. Case 2:14-cv-05824-ES-JAD Document 1 Filed 09/18/14 Page 2 of 35 PageID: 2 The Parties 2. Plaintiff Jazz Pharmaceuticals is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 3180 Porter Drive, Palo Alto, California 94304. 3. On information and belief, defendant Par Pharmaceutical, Inc. is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 300 Tice Boulevard, Woodcliff Lake, New Jersey.
    [Show full text]
  • Penicillin G Potassium Injection, USP
    Penicillin G Potassium Injection, USP In PL 2040 Plastic Container For Intravenous Use Only GALAXY Container (PL 2040 Plastic) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Penicillin G Potassium Injection, USP and other antibacterial drugs, Penicillin G Potassium Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION Penicillin G Potassium, USP is a natural penicillin. It is chemically designated 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,3,3-dimethyl-7-oxo-6­ [(phenylacetyl)amino]-, monopotassium salt, [2S-(2α, 5α, 6β)]. It is crystalline. It is freely soluble in water, in isotonic sodium chloride solution and in dextrose solutions. The structural formula is as shown below. Penicillin G Potassium Injection, USP (equivalent to 1, 2, or 3 million units of penicillin G) is a 50 mL premixed, iso-osmotic, sterile, nonpyrogenic, frozen solution for intravenous administration. Dextrose, USP has been added to the above dosages to adjust osmolality (approximately 2 g, 1.2 g, and 350 mg as dextrose hydrous, respectively). Sodium Citrate, USP has been added as a buffer. The pH has been adjusted with hydrochloric acid and may have been adjusted with sodium hydroxide. The pH is 6.5 (5.5 to 8.0). The solution is contained in a single dose GALAXY container (PL 2040 Plastic) and is intended for intravenous use after thawing to room temperature. This GALAXY container is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach Reference ID: 3960352 out certain chemical components of the plastic in very small amounts within the expiration period.
    [Show full text]
  • Molecular Mechanisms of Antiseizure Drug Activity at GABAA Receptors
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Seizure 22 (2013) 589–600 Contents lists available at SciVerse ScienceDirect Seizure jou rnal homepage: www.elsevier.com/locate/yseiz Review Molecular mechanisms of antiseizure drug activity at GABAA receptors L. John Greenfield Jr.* Dept. of Neurology, University of Arkansas for Medical Sciences, 4301W. Markham St., Slot 500, Little Rock, AR 72205, United States A R T I C L E I N F O A B S T R A C T Article history: The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at Received 6 February 2013 GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by Received in revised form 16 April 2013 the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, Accepted 17 April 2013 actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible Keywords: antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, Inhibition led to the development of ganaxolone. Other agents modulate GABAergic ‘‘tone’’ by regulating the Epilepsy synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane Antiepileptic drugs chloride gradient, which changes during development and in chronic epilepsy. This may provide an GABA receptor Seizures additional target for ‘‘GABAergic’’ ASDs. GABAAR subunit changes occur both acutely during status Chloride channel epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs.
    [Show full text]
  • PRIMAXIN (Imipenem and Cilastatin)
    • Known hypersensitivity to any component of PRIMAXIN (4) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ----------------------- WARNINGS AND PRECAUTIONS ----------------------­ PRIMAXIN safely and effectively. See full prescribing information • Hypersensitivity Reactions: Serious and occasionally fatal for PRIMAXIN. hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. If an allergic reaction PRIMAXIN® (imipenem and cilastatin) for Injection, for to PRIMAXIN occurs, discontinue the drug immediately (5.1). intravenous use • Seizure Potential: Seizures and other CNS adverse reactions, such Initial U.S. Approval: 1985 as confusional states and myoclonic activity, have been reported during treatment with PRIMAXIN. If focal tremors, myoclonus, or --------------------------- RECENT MAJOR CHANGES --------------------------­ seizures occur, patients should be evaluated neurologically, placed Indications and Usage (1.9) 12/2016 on anticonvulsant therapy if not already instituted, and the dosage of Dosage and Administration (2) 12/2016 PRIMAXIN re-examined to determine whether it should be decreased or the antibacterial drug discontinued (5.2). ----------------------------INDICATIONS AND USAGE ---------------------------­ • Increased Seizure Potential Due to Interaction with Valproic Acid: PRIMAXIN for intravenous use is a combination of imipenem, a penem Co-administration of PRIMAXIN, to patients receiving valproic acid antibacterial, and cilastatin, a renal dehydropeptidase inhibitor, or divalproex sodium results in a reduction in valproic acid indicated for the treatment of the following serious infections caused by concentrations. The valproic acid concentrations may drop below designated susceptible bacteria: the therapeutic range as a result of this interaction, therefore • Lower respiratory tract infections. (1.1) increasing the risk of breakthrough seizures. The concomitant use of • Urinary tract infections.
    [Show full text]
  • Proteostasis of Glial Intermediate Filaments: Disease Models, Tools, and Mechanisms
    PROTEOSTASIS OF GLIAL INTERMEDIATE FILAMENTS: DISEASE MODELS, TOOLS, AND MECHANISMS Rachel Anne Battaglia A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell Biology and Physiology in the School of Medicine. Chapel Hill 2021 Approved by: Natasha T. Snider Carol Otey Keith Burridge Douglas Cyr Mohanish Deshmukh Damaris Lorenzo i © 2021 Rachel Anne Battaglia ALL RIGHTS RESERVED ii ABSTRACT Rachel Anne Battaglia: Proteostasis of Glial Intermediate Filaments: Disease Models, Tools, and Mechanisms (Under the direction of Natasha T. Snider) Astrocytes are a major glial cell type that is crucial for the health and maintenance of the Central Nervous System (CNS). They fulfill diverse functions, including synapse formation, neurogenesis, ion homeostasis, and blood brain barrier formation. Intermediate filaments (IFs) are components of the astrocyte cytoskeleton that support many of these functions in healthy individuals. However, upon cellular stress or genetic mutations, IF proteins are prone to accumulation and aggregation. These processes are thought to contribute to disease pathogenesis of different tissue-specific disorders, but therapeutic targeting of IFs is hindered by a lack of pharmacological tools to modulate their assembly and disassembly states. Moreover, the mechanisms that govern the formation and dissolution of IF aggregates are poorly defined. In this dissertation, I investigate IF aggregates called Rosenthal fibers (RFs), which form in astrocytes of patients with two pediatric neurodegenerative diseases, Alexander disease (AxD) and Giant Axonal Neuropathy (GAN). My aim was to gain a better understanding of the mechanisms of how astrocyte IF protein aggregates form and interrogate the role of post- translational modifications (PTMs) in this process.
    [Show full text]
  • Characterization of the GHB Withdrawal Syndrome
    Journal of Clinical Medicine Article Characterization of the GHB Withdrawal Syndrome Casper J. H. Wolf 1,2,3,* , Harmen Beurmanjer 3,4 , Boukje A. G. Dijkstra 3,4 , Alexander C. Geerlings 1 , Marcia Spoelder 2 , Judith R. Homberg 2 and Arnt F. A. Schellekens 1,3 1 Medical Center, Department of Psychiatry, Radboud University, 6525 GA Nijmegen, The Netherlands; [email protected] (A.C.G.); [email protected] (A.F.A.S.) 2 Department of Cognitive Neuroscience, Donders Institute for Brain Cognition and Behaviour, Radboud University, 6525 EN, Nijmegen, The Netherlands; [email protected] (M.S.); [email protected] (J.R.H.) 3 Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), 6525 HR Nijmegen, The Netherlands; [email protected] (H.B.); [email protected] (B.A.G.D.) 4 Novadic-Kentron Addiction Care, 5261 LX Vught, The Netherlands * Correspondence: [email protected] Abstract: The gamma-hydroxybutyric acid (GHB) withdrawal syndrome can have a fulminant course, complicated by severe complications such as delirium or seizures. Detoxification by tapering with pharmaceutical GHB is a safe way to manage GHB withdrawal. However, a detailed description of the course of the GHB withdrawal syndrome is currently lacking. This study aimed to (1) describe the course of GHB withdrawal symptoms over time, (2) assess the association between vital signs and withdrawal symptoms, and (3) explore sex differences in GHB withdrawal. In this observational multicenter study, patients with GHB use disorder (n = 285) were tapered off with pharmaceutical GHB. The most reported subjective withdrawal symptoms (SWS) were related to cravings, fatigue, insomnia, sweating and feeling gloomy.
    [Show full text]
  • The Role of G Protein-Coupled Receptors (Gpcrs) and Calcium Signaling in Schizophrenia
    cells Review The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines Tomasz Boczek 1 , Joanna Mackiewicz 1 , Marta Sobolczyk 1 , Julia Wawrzyniak 1, Malwina Lisek 1, Bozena Ferenc 1, Feng Guo 2 and Ludmila Zylinska 1,* 1 Department of Molecular Neurochemistry, Faculty of Health Sciences, Medical University of Lodz, 92215 Lodz, Poland; [email protected] (T.B.); [email protected] (J.M.); [email protected] (M.S.); [email protected] (J.W.); [email protected] (M.L.); [email protected] (B.F.) 2 Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110122, China; [email protected] * Correspondence: [email protected] Abstract: Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common Citation: Boczek, T.; Mackiewicz, J.; targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through 2+ Sobolczyk, M.; Wawrzyniak, J.; Lisek, several downstream pathways, many of them engaging intracellular Ca mobilization. Dysfunctions M.; Ferenc, B.; Guo, F.; Zylinska, L. of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related The Role of G Protein-Coupled regions are likely to underly the complex picture that includes the whole spectrum of positive Receptors (GPCRs) and Calcium and negative schizophrenia symptoms.
    [Show full text]