Pharmacology. Scopus Biopharma will contract with qualified CRO(s) to perform standard Good Laboratory Practice (GLP) safety pharmacology studies primarily on the cannabidiol component of SB-001. The studies are anticipated to include in vitro hERG, subcutaneous (sc) rat central nervous system, sc rat respiratory system, and sc dog cardiovascular system, as well as additional studies if warranted by the data. All of the GLP safety pharmacology studies will utilize DS from either the engineering or cGMP batches.
Pharmacology. Results of nonclinical pharmacology studies demonstrate the following: • FRα has limited normal tissue expression and marked expression in solid tumors, particularly cancers of the ovary and endometrium (Investigator Brochure). In vitro studies demonstrated that MIRV binds cell surface FRα with high apparent affinity (≤ 0.1 nM) and shows potent (IC50 ≤ 1 nM) and selective cytotoxicity against cells expressing FRα. MIRV-mediated cytotoxicity involves binding, internalization, and degradation of MIRV, which releases DM4. DM4 can be methylated to yield S- methyl-DM4. Both DM4 and S-methyl-DM4 can inhibit tubulin polymerization and microtubule assembly, causing cell death. The lipophilic molecules S-methyl DM4 and DM4 can also diffuse to neighboring cells and induce bystander killing. • In vitro cytotoxicity studies suggest that cells sensitive to MIRV express higher levels of FRα and release 10- to 100-fold more cytotoxic maytansinoid than cells resistant to MIRV. • MIRV retains the inherent activities of its Ab moiety, M9346A, including binding affinity (apparent affinity ≤ 0.1 nM) and selectivity for FRα, capacity for uptake, internalization and degradation by FRα-positive target cells, and ability to induce Ab- dependent cell-mediated cytotoxicity (ADCC) in vitro. • MIRV demonstrates significant activity against FRα-positive xenografts. Partial and/or complete regressions in xenograft models of EOC were seen at doses of MIRV well below its maximum tolerated dose (MTD).
Pharmacology. An immunosuppressive agent that is the active metabolite of azathioprine Licensed use – refer to the SPC for full information Cytotoxic agent. Mercaptopurine is indicated for the treatment of acute leukaemia. It may be utilised in remission induction and it is particularly indicated for maintenance therapy in acute lymphoblastic leukaemia and acute myelogenous leukaemia. Mercaptopurine may be used in the treatment of chronic granulocytic leukaemia. Form and strength of preparation Tablets 50mg. The tablets must be swallowed whole and not chewed. The tablets should not usually be broken or crushed. If halving a tablet is required, care should be taken not to contaminate the hands or inhale the drug. If broken tablets are handled, wash hands immediately. Side effects – refer to the SPC for full information Anorexia, nausea and vomiting, hypersensitivity (fever, rigors, rash), bone marrow suppression, hepatotoxicity, oral ulceration, CNS disturbances (headache, drowsiness, blurred vision), alopecia Rarely: pancreatitis; transient oligospermia (See BNF for comprehensive list) Very rare: Intestinal ulceration; lymphoma Bone marrow suppression: Patients should be warned to report immediately any signs or symptoms of bone marrow suppression e.g. inexplicable bruising, bleeding or infection Drug interactions – refer to the SPC for full information The following have potentially serious interaction with mercaptopurine and caution must be used when prescribing concurrently: Sulfamethoxazole (as co-trimoxazole), trimethoprim, warfarin or acenocoumarol (anticoagulant effect may be inhibited). Aminosalicylate derivatives: Lower doses of mercaptopurine may need to be considered when administered concomitantly with olsalazine, mesalazine or sulfasalazine. Avoid concomitant use of mercaptopurine with allopurinol and febuxostat (unless supervised by a specialist), and with clozapine. Contraindications and precautions – refer to the SPC for full information Contra-indications: Hypersensitivity to azathioprine / mercaptopurine Thiopurine methyltransferase deficiency (see below) Cautions: Pregnancy: Mercaptopurine should not be given to patients who are pregnant or likely to become pregnant without careful assessment of risk versus benefit. Hepatic impairment: May need to reduce dose Renal insufficiency: Reduce dose for those patients with moderate to severe renal impairment (GFR<10ml/minute; serum creatinine >300micromol/litre) In general patients should avoid “live” vaccine...
Pharmacology. BAB (OPG Farma, Utrecht, The Netherlands) was added to the extracellular solution from a stock of BAB in ethanol (1−500 mM). Final ethanol concentration never exceeded 0.1 %. Because BAB has low water solubility (<700 µM at room temperature, Merck Index 1989) and easily binds to plastic surfaces of the perfusion system, final BAB concentrations up to 500 µM were verified using absorption spectrophotometry (290 nm). m−Conotoxin−GVIA (CnTx; Peptide Institute Inc., Osaka, Japan) was dissolved in distilled water and added with a final fully blocking concentration of 3.3 or 5 µM (Xxxxxxx et al., 1995; Xxxxxxx and Xxx, 1992a; Xxxxx and Xxxx, 2002; Xxxxxxx and Xxx, 1992b). Analysis and statistics Normalized data were corrected for rundown in the presence of vehicle (0.1 % ethanol) at all potentials measured in control experiments (n = 8). For example, at test pulses of 0 mV an apparent linear barium current decline (rundown) of ~ 6 % in 5 min was observed. The concentration−inhibition data were fitted using the Hill equation: I/Io = (1 + ([BAB]/IC50)n)−1, where the IC50 is the concentration at which the current is reduced by 50% and n is the Hill coefficient. Results are presented as mean ± standard deviation (M ± SD) for n cells, unless stated otherwise, and compared using paired or independent t−tests with the level of significance (p) chosen as 0.05.
Pharmacology. Ciclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells. Ciclosporin is an immunomodulator which acts upon T lymphoctes. Ciclosporin suppresses the immune system by preventing T lymphocytes from producing lymphokines. Lymphokines normally stimulate the growth of T and B lymphocytes, which are cells responsible for regulating and triggering immune responses. T cells are involved in producing inflammation as part of their immune function. Suppressing their action can help to reduce the inflammation in the joints of people who have rheumatoid arthritis or reduce inflammation in the skin of people who have cutaneous inflammatory conditions. Ciclosporin can promote a Th1 response in atopic dermatitis, altering IL-4 transcription and monocyte IL-10 production. Ciclosporin also has a direct effect on keratinocytes. 40% of an oral dose of ciclosporin is absorbed from the gut. Metabolism is hepatic and excretion is mostly in the bile with only 6% via urinary tract. Licensed use • Prevention of organ rejection • Treatment of rheumatoid arthritis and psoriasis • Short term treatment of severe atopic dermatitis Non licensed dermatological indications include: Behcet’s disease, Chronic idiopathic urticaria, Connective tissue disease, immunobullous disease, Pyoderma gangrenosum, photodermatoses. Form and strength of preparation and dosages Ciclosporin (oral solution or soft gelatin capsule) given twice a day based on patient’s weight, initially 2.5mg/kg/day. Available in 10mg, 25mg, 50mg or 100mg gelatin capsules or 100mg/ml solution. The solution can be mixed with fruit juice to improve the taste, but not grapefruit juice (this contains the flavinoid narigenin which inhibits CYP 3A4 activity and can increase plasma concentration of ciclosporin). Ciclosporin is given in divided doses from 2.5 to 4mg/kg/day in rheumatoid arthritis, and 2.5 to 5mg/kg/day in dermatology. Side effects • Tingling and numbness in the hands and feet: This usually subsides with time. • Trembling hands and feet and muscle cramps: Tonic water may help to alleviate any cramp pain. • Hypertrichosis: Increased growth of body ha...
Pharmacology. Colistin belongs to the polymyxin group of antibiotics. The polymyxins are cationic agents that work by damaging the cell membrane of bacteria that have a hydrophobic outer membrane (such as P.aeruginosa) Licensed use Treatment by inhalation of Pseudomonas aeruginosa lung infection. Therapeutics Advisory Group (TAG) is the Area Prescribing Committee (APC) for CCGs in Norfolk & Waveney Form and strength of preparation Colistin 1,000,000 units (= 1 mega unit) per vial Colistin 2,000,000 units (= 2 mega units) per vial Side effects – for a full list of side-effects please see the manufacturer’s SPC Inhalation may induce coughing or bronchospasm. Sore throat has also been reported. Due to negligible systemic absorption of colistin from the lung, the risk of systemic toxicity is low. Skin rashes have occurred during nebulised treatment. They may be a sign of hypersensitivity and will require treatment to be stopped. Drug interactions Trans-pulmonary absorption of colistin is considered to be negligible; therefore no significant interactions with systemic medication are anticipated. There are no known interactions with other inhaled/nebulised therapies. Contraindications and precautions Bronchospasm can occur. As a precaution the first (test) dose must be given under supervision, with lung function tests before and after to ensure continued suitability. Hypersensitivity to colistin or polymyxin B Patients with myasthenia gravis Criteria for patient selection Patients with bronchiectasis who grow Pseudomonas aeruginosa in their sputum or cough swab and who have required repeated admissions to hospital for IV treatment. Initiation of therapy – by whom? Treatment should only be initiated by a respiratory physician. Initial dose and administration Initial (test) dose will be given in hospital by a respiratory nurse with spirometry before and after to assess tolerability. In children who are too young to perform spirometry, assessment of tolerability will be made clinically by the specialist nurse who is administering the test dose. Maintenance dose and administration Child (1 month – 2 years): 500,000 units -1 mega unit BD Child (2-18 years): 1-2 mega units BD Adult: 2 mega units BD Reconstitution: The method used for the test dose should be continued. Any change in the diluents used will require the test dose to be repeated. Method 1: 5ml sodium chloride 0.9% Method 2: 2ml water + 2ml sodium chloride 0.9% (least likely to cause bronchoconstriction...
Pharmacology. Duloxetine is a combined serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor. It weakly inhibits reuptake, with no significant affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. In animal studies, increased levels of 5-HT and NE in the sacral spinal cord lead to increased urethral tone via enhanced nerve stimulation to the urethral striated sphincter muscle only during the storage phase of the micturition cycle. A similar mechanism in women is believed to result in stronger urethral closure during urine storage with physical stress that could explain the efficacy of duloxetine in the treatment of women with SUI. Licensed use For the treatment of moderate to severe stress urinary incontinence (SUI) in women. Form and strength of preparation 20mg and 40mg capsules Side effects
Pharmacology. Introduction Pharmacology course for dental students is comprised of about 60-h lecture and 55-h seminars based learning. The course is performed in their third and fifth year of training. Students learn the general principals of drug action and drug disposition in the body and study the effects of disease, pregnancy, and extremes of age on drug handling. They gain the knowledge of adverse drug reactions, drug interactions and effects of drug on infants when these are given to nursing mothers. Primary Aims • To provide dental students with: • An understanding of principles of drug absorption, distribution, metabolism, excretion, mode of action and adverse drug reactions. • Knowledge of drugs used in dentistry, the relevance of a concurrent medical condition and its therapy, the use of drug in pregnancy, lactation and extremes of age. Main Objectives By the end of the course, students will be able to: • Describe methods of drug absorption, distribution, metabolism and excretion. • List the principles of drug action and drugs acting on the autonomic system. • List the actions of important autacoids and their antagonists. • List the actions of important drugs • List the groups of drug used in dentistry, their modes of action, metabolism, adverse reactions, precautions and interactions with other drugs. • List the cardiovascular drugs, drugs used in diseases of respiratory system, drugs affecting central nervous system, renal functions and anticancer drugs • Describe the precautions in prescribing drugs for pregnant and lactating women. • Describe the precautions in prescribing drugs for patients particularly susceptible because of their age or a prevailing medical condition. • Write a legal prescription for a dental patient with knowledge of drug schedules and controlled drugs under the current regulations. Hours in the Curriculum The course comprises of 2 hours of lectures and 2 hours of seminar weekly in third year of the studies. Teaching terms for dental students are longer than the traditional university terms. Currently each PBL session is of 90-minute duration. Fifteen hours of seminar are on the fifth year of training dealing with clinical pharmacology for dental students. Methods of Learning/Teaching Students learn Pharmacology from traditional lectures and from Pharmacology books. They also learn about drug treatment of various dental conditions from an extensive range of dental and medical problems under the PBL programme, which is continuously rev...
Pharmacology. Memantine is a voltage-dependent, moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks the effects of pathologically elevated toxic levels of glutamate that may lead to neuronal dysfunction. Licensed use Treatment of patients with moderate to severe Alzheimer's disease. Form and strength of preparation Memantine 4-week treatment initiation pack containing 5mg, 10mg, 15mg and 20mg tablets Memantine 10mg and 20mg film-coated tablets Memantine 5mg/pump oral solution Side effects The most frequently occurring side effects with a higher incidence for memantine than placebo are dizziness (6.3% vs. 5.6%), headache (5.2% vs. 3.9%), constipation (4.6% vs. 2.6%), somnolence (3.4% vs. 2.2%) and hypertension (4.1% vs. 2.8%). Other common adverse events (>1/100 to <1/10) are hypersensitivity and dyspnoea. Drug interactions Memantine is only minimally metabolised, does not inhibit CYP1A2, 2A6, 2C9, 2D6, 2E1 or 3A, or the FMO system, or epoxide hydrolase or sulphation, and so metabolic interactions are unlikely. Raised urinary pH (e.g. infections, diet change, excessive alkalising gastric buffers, etc) may significantly reduce excretion. Plasma protein binding is 45%. Amantadine: Both are NMDA-antagonists and the combination should be avoided as CNS adverse effects may be more frequent. Care also with ketamine and dextromethorphan. Anticholinergics: The anticholinergic’s effects may be enhanced by memantine. Anticholinesterases: No interaction Antipsychotics: Antipsychotic effects may be reduced by memantine. Dopamine agonists: Bromocriptine may be enhanced by memantine. Levodopa: The effects of levodopa may be enhanced by memantine. Smoking: There is a theoretical potential for increased memantine plasma levels. Contraindications and precautions Caution is recommended in patients with epilepsy. Avoid with NMDA-antagonists such as amantadine, ketamine or dextromethorphan. Do not use oral solution (which contains sorbitol) in people with fructose intolerance. Slow pulse Do not use in pregnancy unless clearly necessary. Women taking memantine should not breast feed. Initiation of therapy – by whom?
Pharmacology. Methylphenidate, dexamfetamine and lisdexamfetamine (a pro-drug for dexamfetamine) are centrally-acting sympathomimetics. Their mechanism of action is mainly through inhibition of noradrenaline and dopamine transporters. Methylphenidate and lisdexamfetamine are the NICE treatments of first choice. Atomoxetine is a noradrenaline reuptake inhibitor which indirectly boosts dopamine. Licensed use Drug prescribing in adults is usually off-label. Exceptions are atomoxetine, which is licensed for new treatment in adults with ADHD symptoms that can be confirmed from childhood, and lisdexamfetamine (as Elvanse Adult®) and Medikinet XL which is indicated as part of a comprehensive treatment programme for attention deficit/hyperactivity disorder (ADHD) in adults. Clinicians are supported in prescribing for adults with ADHD by the NICE NG 87, BAP (British Association of Psychopharmacology) guidelines. Forms and strengths of preparations Three types of methylphenidate multiphasic XL preparations are available: • Concerta XL®, Matoride XL®, Xenidate XL® , Delmosart® or Xaggitin XL® tablets (22% Immediate Release [IR], 78% extended release [XL]) (See Appendix 1 for comparative costs of these once-daily methylphenidate products) • Equasym XL® capsules (30% IR, 70% XL) • Medikinet XL® capsules (50% IR, 50% XL) These different types of products are not interchangeable and the BNF recommends prescribing by brand name to avoid the risk of destabilisation from different release characteristics of the XL products dispensed generically. Strengths of Methylphenidate modified-release products: (22% Immediate Release [IR], 78% extended release [XL]) Concerta XL®: capsule-shaped tablets with internal hard membrane, 18mg (equivalent to 15mg of plain tablets), 27mg, 36mg or 54mg in packs of 28, or 30 Matoride XL®: cylindrical tablets with internal hard membrane, 18mg (equivalent to 15mg of plain tablets), 36mg or 54mg in packs of 28, 30, 60 or 90 Xenidate XL®: round, biconvex tablets, 18mg (equivalent to 15mg of plain tablets), 27mg, 36mg or 54mg in packs of 28, 30 or 100 Delmosart®: capsule-shaped, biconvex tablets, 18mg (equivalent to 15mg of plain tablets), 27mg, 36mg or 54mg in packs of 28, 30 or 90 Xaggitin XL®: capsule-shaped, biconvex tablets, 18mg (equivalent to 15mg of plain tablets), 27mg, 36mg or 54mg in packs of 28, 30 or 90 (See Appendix 1 for comparative costs of these methylphenidate products) Equasym XL®: (30% IR, 70% XL) capsules with small globules inside, 10mg, 20mg...
