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. 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. For the treatment of moderate to severe stress urinary incontinence (SUI) in women. 20mg and 40mg capsules
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). 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. • 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. 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. • 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 hair can be removed by shaving, waxing or using a cream hair remover. A c...
Pharmacology. Naltrexone is a competitive opioid receptor antagonist, and will block the effects of all opioids. It is thought to diminish the reinforcement which promotes drinking behaviour in alcohol use disorders by blocking the effect of alcohol-induced -endorphin release in the nucleus accumbens and the ventral tegmental area which are involved in the reward circuit in the brain. Naltrexone is licensed in the UK and recommended as a treatment option for AUD according to NICE (Clinical Guideline 115, February 2011 xxxx://xxx.xxxx.xxx.xx/guidance/CG115 ). 50mg tablets, scored Concomitant administration of naltrexone with an opioid-containing medication should be avoided. Patients should be warned that attempts to overcome the blockade may result in acute opioid intoxication which may be life threatening. Contraindications Patients currently dependent on opioids since an acute withdrawal syndrome may ensue. Patients who are currently taking medication containing opioids. Patients who are hypersensitive to naltrexone. Patients with acute hepatitis or liver failure. Patients with severe renal impairment. Precautions Clients who are breast-feeding, pregnant or planning to become pregnant - Animal studies do not suggest a teratogenic effect. Because of absence of documented clinical experience naltrexone should only be given to pregnant or breast-feeding women when, in the judgement of the clinician, the potential benefits outweigh the possible risks. In an emergency requiring opioid analgesia an increased dose of opioid may be required. The patient should be closely monitored for evidence of respiratory depression or other adverse symptoms. Patents should be warned of this risk and advised to alert treating doctors. See manufacturer’s Patient Information Leaflet - Link. Specialist alcohol services Half a tablet each day for one week (25mg/day) then one tablet daily (50mg/day) 50mg daily. Naltrexone can also be given at extended intervals up to 72 hours by increasing the dose as follows: 24 hour interval – 50mg 48 hour interval – 100mg 72 hour interval - 150mg The naltrexone SPC states “The dosage-regimen can (therefore) be modified in order to improve compliance to a three-times-a- week dosing schedule as follows: administration of 2 tablets (=100 mg naltrexone hydrochloride) on Monday and on Wednesday and 3 tablets (=150 mg naltrexone hydrochloride) on Friday” The evidence base does not offer clear guidance as to the duration of therapy. The prescription should be revi...
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. Treatment of patients with moderate to severe Alzheimer's disease. 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 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. 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. 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.
Pharmacology. We will perform a postpartum treatment with both oxytocin or carbetocin using as readouts the behavioral and neurochemical parameters outlined above. In addition, we will study the effects of treatments with L-DOPA plus a decarboxylase inhibitor, with a negative allosteric modulator of mGlu5 receptors (MTEP), or with a positive allosteric modulator of mGlu4 receivers (PHCCC).
Pharmacology. Sirolimus is a selective immunosuppressant which inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12 and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition of mTOR results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression. Sirolimus is licensed for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk who have received a renal transplant. It is recommended that sirolimus is used initially in combination with ciclosporin and corticosteroids for 2–3 months. The marketing authorisation states that sirolimus may be continued as maintenance therapy with corticosteroids only if ciclosporin can be progressively discontinued. 500 microgram tablets,1 mg coated tablets, 2 mg coated tablets and 1mg/ml oral solution. (NB The BNF states that the 500 microgram tablet is not bioequivalent to the 1 mg and 2 mg tablets. Multiples of 500 microgram tablets should not be used as a substitute for other tablet strengths) The most commonly reported adverse drug reactions (occurring in >10% of patients) are: thrombocytopenia, anaemia, hypokalaemia, urinary tract infection, hypercholesterolaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, and increased blood lactate dehydrogenase (LDH). Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin. Hepatotoxicity has been reported; the risk may increase as the trough sirolimus level increases. There have been rare reports of fatal hepatic necrosis with elevated trough sirolimus levels. Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the interstitial lung disease has ...
Pharmacology. [information has been omitted from the filed version of this License Agreement]
