The latest set of opinions from advisors to the European Medicines Agency include recommendations to approve six new medicines, including Bristol-Myers Squibb’s new hepatitis C drug and Eli Lilly’s biosimilar of the Sanofi diabetes blockbuster Lantus.
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Biomarker predicts effectiveness of brain cancer treatment
Researchers at the University of California, San Diego School of Medicine have identified a new biomarker that predicts whether glioblastoma – the most common form of primary brain cancer – will respond to chemotherapy. The findings are published in the July print issue of Oncotarget.
“Every patient diagnosed with glioblastoma is treated with a chemotherapy called temozolomide. About 15 percent of these patients derive long-lasting benefit,” said Clark C. Chen, MD, PhD, vice-chairman of Academic Affairs, Division of Neurosurgery, UC San Diego School of Medicine and the study’s principal investigator. “We need to identify which patients benefit from temozolomide and which another type of treatment. All therapies involve risk and the possibility of side-effects. Patients should not undergo therapies if there’s no likelihood of benefit.”
To pinpoint which patients were most likely respond to temozolomide, the researchers studied microRNAs that control the expression of a protein called methyl-guanine-methyl-transferase…
View original post 163 more words
Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor…….
AMPRENAVIR
Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.
Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available.
| Systematic (IUPAC) name | |
|---|---|
| (3S)-oxolan-3-yl N-[(2S,3R)-3-hydroxy-4-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-1-phenylbutan-2-yl]carbamate | |
| Clinical data | |
| Trade names | Agenerase |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a699051 |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. | C (US) |
| Routes | oral |
| Pharmacokinetic data | |
| Protein binding | 90% |
| Metabolism | hepatic |
| Half-life | 7.1-10.6 hours |
| Excretion | <3% renal |
| Identifiers | |
| CAS number | 161814-49-9  |
| ATC code | J05AE05 |
| PubChem | CID 65016 |
| DrugBank | DB00701 |
| ChemSpider | 58532 |
| UNII | 5S0W860XNR |
| KEGG | D00894 |
| ChEBI | CHEBI:40050 |
| ChEMBL | CHEMBL116 |
| NIAID ChemDB | 006080 |
| Chemical data | |
| Formula | C25H35N3O6S |
| Mol. mass | 505.628 g/mol |
Amprenavir (Agenerase, GlaxoSmithKline) is a protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules.
Production of amprenavir was discontinued by the manufacturer December 31, 2004; a prodrug version (fosamprenavir) is available
………………….
New approaches to the industrial synthesis of HIV protease inhibitors
http://pubs.rsc.org/en/content/articlelanding/2004/ob/b404071f/unauth#!divAbstract
Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.
…………………………………………………………………
AGENERASE (amprenavir) is an inhibitor of the human immunodeficiency virus (HIV) protease. The chemical name of amprenavir is (3S)-tetrahydro-3-furyl N-[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hydroxypropyl]carbamate. Amprenavir is a single stereoisomer with the (3S)(1S,2R) configuration. It has a molecular formula of C25H35N3O6S and a molecular weight of 505.64. It has the following structural formula:
 |
Amprenavir is a white to cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C.
AGENERASE Capsules (amprenavir capsules) are
available for oral administration. Each 50- mg capsule contains the inactive ingredients d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), polyethylene glycol 400 (PEG 400) 246.7 mg, and propylene glycol 19 mg. The capsule shell contains the inactive ingredients d-sorbitol and sorbitans solution, gelatin, glycerin, and titanium dioxide. The soft gelatin capsules are printed with edible red ink. Each 50- mg AGENERASE Capsule contains 36.3 IU vitamin E in the form of TPGS. The total amount of vitamin E in the recommended daily adult dose of AGENERASE is 1,744 IU.
See also
- Fosamprenavir, a prodrug of amprenavir
External links
- Amprenavir bound to proteins in the PDB
Luseogliflozin, TS 071…………. strongly inhibited SGLT2 activity,
LUSEOGLIFLOZIN, CAS 898537-18-3
An antidiabetic agent that inhibits sodium-dependent glucose cotransporter 2 (SGLT2).
(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol
(1S)-1,5-anhydro-1-[3-(4-ethoxybenzyl)-6-methoxy-4-methylphenyl]-1-thio-D-glucitol
Taisho Pharmaceutical Co., Ltd
Taisho (Originator), PHASE 3
Click to access 2013041801-e.pdf
TS-071
| Taisho Pharmaceutical Holdings Co. Ltd. | |
| Description | Oral sodium-glucose cotransporter 2 (SGLT2) inhibitor |
TS-071, an SGLT-2 inhibitor, is in phase III clinical development at Taisho for the oral treatment of type 1 and type 2 diabetes
In 2012, the product was licensed to Novartis and Taisho Toyama Pharmaceutical by Taisho in Japan for comarketing for the treatment of type 2 diabetes.
Diabetes is a metabolic disorder which is rapidly emerging as a global health care problem that threatens to reach pandemic levels. The number of people with diabetes worldwide is expected to rise from 285 million in 2010 to 438 million by 2030. Diabetes results from deficiency in insulin because of impaired pancreatic β-cell function or from resistance to insulin in body, thus leading to abnormally high levels of blood glucose.
Diabetes which results from complete deficiency in insulin secretion is Type 1 diabetes and the diabetes due to resistance to insulin activity together with an inadequate insulin secretion is Type 2 diabetes. Type 2 diabetes (Non insulin dependent diabetes) accounts for 90-95 % of all diabetes. An early defect in Type 2 diabetes mellitus is insulin resistance which is a state of reduced responsiveness to circulating concentrations of insulin and is often present years before clinical diagnosis of diabetes. A key component of the pathophysiology of Type 2 diabetes mellitus involves an impaired pancreatic β-cell function which eventually contributes to decreased insulin secretion in response to elevated plasma glucose. The β-cell compensates for insulin resistance by increasing the insulin secretion, eventually resulting in reduced β-cell mass. Consequently, blood glucose levels stay at abnormally high levels (hyperglycemia).
Hyperglycemia is central to both the vascular consequences of diabetes and the progressive nature of the disease itself. Chronic hyperglycemia leads to decrease in insulin secretion and further to decrease in insulin sensitivity. As a result, the blood glucose concentration is increased, leading to diabetes, which is self-exacerbated. Chronic hyperglycemia has been shown to result in higher protein glycation, cell apoptosis and increased oxidative stress; leading to complications such as cardiovascular disease, stroke, nephropathy, retinopathy (leading to visual impairment or blindness), neuropathy, hypertension, dyslipidemia, premature atherosclerosis, diabetic foot ulcer and obesity. So, when a person suffers from diabetes, it becomes important to control the blood glucose level. Normalization of plasma glucose in Type 2 diabetes patients improves insulin action and may offset the development of beta cell failure and diabetic complications in the advanced stages of the disease.
Diabetes is basically treated by diet and exercise therapies. However, when sufficient relief is not obtained by these therapies, medicament is prescribed alongwith. Various antidiabetic agents being currently used include biguanides (decrease glucose production in the liver and increase sensitivity to insulin), sulfonylureas and meglitinides (stimulate insulin production), a-glucosidase inhibitors (slow down starch absorption and glucose production) and thiazolidinediones (increase insulin sensitivity). These therapies have various side effects: biguanides cause lactic acidosis, sulfonylurea compounds cause significant hypoglycemia, a-glucosidase inhibitors cause abdominal bloating and diarrhea, and thiazolidinediones cause edema and weight gain. Recently introduced line of therapy includes inhibitors of dipeptidyl peptidase-IV (DPP-IV) enzyme, which may be useful in the treatment of diabetes, particularly in Type 2 diabetes. DPP-IV inhibitors lead to decrease in inactivation of incretins glucagon like peptide- 1 (GLP-1) and gastric inhibitory peptide (GIP), thus leading to increased production of insulin by the pancreas in a glucose dependent manner. All of these therapies discussed, have an insulin dependent mechanism.
Another mechanism which offers insulin independent means of reducing glycemic levels, is the inhibition of sodium glucose co-transporters (SGLTs). In healthy individuals, almost 99% of the plasma glucose filtered in the kidneys is reabsorbed, thus leading to only less than 1% of the total filtered glucose being excreted in urine. Two types of SGLTs, SGLT-1 and SGLT-2, enable the kidneys to recover filtered glucose. SGLT-1 is a low capacity, high-affinity transporter expressed in the gut (small intestine epithelium), heart, and kidney (S3 segment of the renal proximal tubule), whereas SGLT-2 (a 672 amino acid protein containing 14 membrane-spanning segments), is a low affinity, high capacity glucose ” transporter, located mainly in the S 1 segment of the proximal tubule of the kidney. SGLT-2 facilitates approximately 90% of glucose reabsorption and the rate of glucose filtration increases proportionally as the glycemic level increases. The inhibition of SGLT-2 should be highly selective, because non-selective inhibition leads to complications such as severe, sometimes fatal diarrhea, dehydration, peripheral insulin resistance, hypoglycemia in CNS and an impaired glucose uptake in the intestine.
Humans lacking a functional SGLT-2 gene appear to live normal lives, other than exhibiting copious glucose excretion with no adverse effects on carbohydrate metabolism. However, humans with SGLT-1 gene mutations are unable to transport glucose or galactose normally across the intestinal wall, resulting in condition known as glucose-galactose malabsorption syndrome.
Hence, competitive inhibition of SGLT-2, leading to renal excretion of glucose represents an attractive approach to normalize the high blood glucose associated with diabetes. Lower blood glucose levels would, in turn, lead to reduced rates of protein glycation, improved insulin sensitivity in liver and peripheral tissues, and improved cell function. As a consequence of progressive reduction in hepatic insulin resistance, the elevated hepatic glucose output which is characteristic of Type 2 diabetes would be expected to gradually diminish to normal values. In addition, excretion of glucose may reduce overall caloric load and lead to weight loss. Risk of hypoglycemia associated with SGLT-2 inhibition mechanism is low, because there is no interference with the normal counter regulatory mechanisms for glucose.
The first known non-selective SGLT-2 inhibitor was the natural product phlorizin
(glucose, 1 -[2-P-D-glucopyranosyloxy)-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)- 1 – propanone). Subsequently, several other synthetic analogues were derived based on the structure of phlorizin. Optimisation of the scaffolds to achieve selective SGLT-2 inhibitors led to the discovery of several considerably different scaffolds.
C-glycoside derivatives have been disclosed, for example, in PCT publications
W.O20040131 18, WO2005085265, WO2006008038, WO2006034489, WO2006037537, WO2006010557, WO2006089872, WO2006002912, WO2006054629, WO2006064033, WO2007136116, WO2007000445, WO2007093610, WO2008069327, WO2008020011, WO2008013321, WO2008013277, WO2008042688, WO2008122014, WO2008116195, WO2008042688, WO2009026537, WO2010147430, WO2010095768, WO2010023594, WO2010022313, WO2011051864, WO201 1048148 and WO2012019496 US patents US65151 17B2, US6936590B2 and US7202350B2 and Japanese patent application JP2004359630. The compounds shown below are the SGLT-2 inhibitors which have reached advanced stages of human clinical trials: Bristol-Myers Squibb’s “Dapagliflozin” with Formula A, Mitsubishi Tanabe and Johnson & Johnson’s “Canagliflozin” with Formula B, Lexicon’s “Lx-421 1″ with Formula C, Boehringer Ingelheim and Eli Lilly’s “Empagliflozin” with Formula D, Roche and Chugai’s “Tofogliflozin” with Formula E, Taisho’s “Luseogliflozin” with Formula F, Pfizer’ s “Ertugliflozin” with Formula G and Astellas and Kotobuki’s “Ipragliflozin” with Formula H.
Formula G Formula H
In spite of all these molecules in advanced stages of human clinical trials, there is still no drug available in the market as SGLT-2 inhibitor. Out of the potential candidates entering the clinical stages, many have been discontinued, emphasizing the unmet need. Thus there is an ongoing requirement to screen more scaffolds useful as SGLT-2 inhibitors that can have advantageous potency, stability, selectivity, better half-life, and/ or better pharmacodynamic properties. In this regard, a novel class of SGLT-2 inhibitors is provided herein
………………………
SYNTHESIS
- Example 5
Synthesis of 2,3,4,6-tetra-O-benzyl-1-C-[2-methoxy-4-methyl-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose
-
Five drops of 1,2-dibromoethane were added to a mixture of magnesium (41 mg, 1.67 mmol), 1-bromo-3-(4-ethoxybenzyl)-6-methoxy-4-methylbenzene (0.51 g, 1.51 mmol) and tetrahydrofuran (2 mL). After heated to reflux for one hour, this mixture was allowed to stand still to room temperature to prepare a Grignard reagent. A tetrahydrofuran solution (1.40 mL) of 1.0 M i-propyl magnesium chloride and the prepared Grignard reagent were added dropwise sequentially to a tetrahydrofuran (5 mL) solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (0.76 g, 1.38 mmol) while cooled on ice and the mixture was stirred for 30 minutes. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate =4:1) to obtain (0.76 g, 68%) a yellow oily title compound.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (t, J=6.92 Hz, 3 H) 2.21 (s, 3 H) 3.51 – 4.20 (m, 12 H) 3.85 – 3.89 (m, 3 H) 4.51 (s, 2 H) 4.65 (d, J=10.72 Hz, 1 H) 4.71 (d, J=5.75 Hz, 1 H) 4.78 – 4.99 (m, 3 H) 6.59 – 7.43 (m, 26 H)
Example 6
-
[0315]
Synthesis of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol
-
An acetonitrile (18 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-5-thio-D-glucopyranose (840 mg, 1.04 mmol) was added sequentially with Et3SiH (0.415 mL, 2.60 mmol) and BF3·Et2O (0.198 mL, 1.56 mmol) at -18°C and stirred for an hour. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (640 mg, 77%).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=6.88 Hz, 3 H) 2.21 (s, 3 H) 3.02 – 3.21 (m, 1 H) 3.55 (t,J=9.40 Hz, 1 H) 3.71 (s, 1 H) 3.74 – 3.97 (m, 10 H) 4.01 (s, 1 H) 4.45 – 4.56 (m, 3 H) 4.60 (d, J=10.55 Hz, 2 H) 4.86 (s, 2 H) 4.90 (d, J=10.55 Hz, 1H) 6.58 – 6.76 (m, 5 H) 6.90 (d, J=7.34 Hz, 1 H) 7.09 – 7.19 (m, 5 H) 7.23 – 7.35 (m, 15 H).
ESI m/z = 812 (M+NH4).
Example 7
Synthesis of (1S)-1,5-anhydro-1-[3-(4-ethoxybenzyl)-6-methoxy-4-methylphenyl]-1-thio-D-glucitol
-
A mixture of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-methoxy-4-methyl-5-(4-ethoxybenzyl)phenyl]-1-thio-D-glucitol (630 mg, 0.792 mmol), 20% palladium hydroxide on activated carbon (650 mg) and ethyl acetate (10 mL) – ethanol (10 mL) was stirred under hydrogen atmosphere at room temperature for 66 hours. The insolubles in the reaction mixture were filtered off with celite and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol =10:1) to obtain a colorless powdery title compound (280 mg, 81%) as 0.5 hydrate. 1H NMR (600 MHz, METHANOL- d4) δ ppm 1.35 (t, J=6.9 Hz, 3 H) 2.17 (s, 3 H) 2.92 – 3.01 (m, 1 H) 3.24 (t, J=8.71 Hz, 1 H) 3.54 – 3.60 (m, 1 H) 3.72 (dd, J=11.5, 6.4 Hz, 1 H) 3.81 (s, 3 H) 3.83 (s, 2 H) 3.94 (dd, J=11.5, 3.7 Hz, 1 H) 3.97 (q, J=6.9 Hz, 2 H) 4.33 (s, 1 H) 6.77 (d, J=8.3 Hz, 2 H) 6.76 (s, 1 H) 6.99 (d, J=8.3 Hz, 2 H) 7.10 (s, 1 H). ESI m/z = 452 (M+NH4+), 493 (M+CH3CO2-). mp 155.0-157.0°C. Anal. Calcd for C23H30O6S·0.5H2O: C, 62.28; H, 7.06. Found: C, 62.39; H, 7.10.
………………………………..
PAPER
(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (TS-071) is a Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for Type 2 Diabetes Treatment
(Journal of Medicinal Chemistry) Saturday March 20th 2010
Author(s): ,
DOI:10.1021/jm901893x
GO TO: [Article]
http://pubs.acs.org/doi/abs/10.1021/jm901893x
(1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (3p)
Compound 3p (0.281 g, 81%) was prepared as a colorless powder from 21p (0.630 g, 0.792 mmol) according to the method described for the synthesis of 3a. (Method A)
mp 155.0−157.0 °C.
1H NMR (600 MHz, MeOH-d4) δ 1.35 (t, J = 6.9 Hz, 3 H), 2.17 (s, 3 H), 2.92−3.01 (m, 1 H), 3.24 (t, J = 8.7 Hz, 1 H), 3.54−3.60 (m, 1 H), 3.72 (dd, J = 6.4, 11.5, Hz, 1 H), 3.81 (s, 3 H), 3.83 (s, 2 H), 3.94 (dd, J = 3.7, 11.5 Hz, 1 H), 3.97 (q, J = 6.9 Hz, 2 H), 4.33 (brs, 1 H), 6.77 (d, J = 8.3 Hz, 2 H), 6.76 (s, 1 H), 6.99 (d, J = 8.3 Hz, 2 H), 7.10 (s, 1 H).
MS (ESI) m/z 452 (M+NH4).
Anal. Calcd for (C23H30O6S·0.5H2O) C, 62.28; H, 7.06. Found C, 62.39; H, 7.10.
3p is compd
| cmpds | R1 | R2 | R3 | SGLT2 (nM) mean (95% CI) | SGLT1 (nM) mean (95% CI) | T1/T2 selectivity |
|---|---|---|---|---|---|---|
| 1 | 27.8 (21.8−35.3) | 246 (162−374) | 8.8 | |||
| 3a | H | H | OEt | 73.6 (51.4−105) | 26100 (20300−33700) | 355 |
| 3b | H | OH | OEt | 283 (268−298) | 14600 (11500−18500) | 51.6 |
| 3c | H | OMe | OEt | 13.4 (11.3−15.8) | 565 (510−627) | 42.2 |
| 3d | H | F | OEt | 9.40 (5.87−15.0) | 7960 (7180−8820) | 847 |
| 3e | H | Me | OEt | 2.29 (1.76−2.99) | 671 (230−1960) | 293 |
| 3f | H | Cl | OEt | 1.77 (0.95−3.30) | 1210 (798−1840) | 684 |
| 3g | OH | H | OEt | 17.4 (15.9−19.0) | 4040 (1200−13600) | 232 |
| 3h | OMe | H | OEt | 37.9 (26.4−54.4) | 100000 (66500−151000) | 2640 |
| 3i | OMe | OMe | OEt | 10.8 (6.84−17.1) | 4270 (1560−11600) | 395 |
| 3j | H | Cl | OMe | 1.68 (1.08−2.60) | 260 (72.5−931) | 155 |
| 3k | H | Cl | Me | 1.37 (0.97−1.95) | 209 (80.2−545) | 153 |
| 3l | H | Cl | Et | 1.78 (0.88−3.63) | 602 (473−767) | 338 |
| 3m | H | Cl | iPr | 4.01 (1.75−9.17) | 8160 (4860−13700) | 2040 |
| 3n | H | Cl | tBu | 18.8 (11.0−32.1) | 35600 (31900−39800) | 1890 |
| 3o | H | Cl | SMe | 1.16 (0.73−1.85) | 391 (239−641) | 337 |
| 3p | OMe | Me | OEt | 2.26 (1.48−3.43) | 3990 (2690−5920) | 1770 |
| 3q | OMe | Me | Et | 1.71 (1.19−2.46) | 2830 (1540−5200) | 1650 |
| 3r | OMe | Me | iPr | 2.68 (2.15−3.34) | 17300 (14100−21100) | 6400 |
| 3s | OMe | Cl | Et | 1.51 (0.75−3.04) | 3340 (2710−4110) | 2210 |
PATENT
| Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2004014930A1 * | Aug 8, 2003 | Feb 19, 2004 | Asanuma Hajime | PROCESS FOR SELECTIVE PRODUCTION OF ARYL 5-THIO-β-D- ALDOHEXOPYRANOSIDES |
NON-PATENT CITATIONS
| Reference | ||
|---|---|---|
| 1 | * | AL-MASOUDI, NAJIM A. ET AL: “Synthesis of some novel 1-(5-thio-.beta.-D-glucopyranosyl)-6-azaur acil derivatives. Thio sugar nucleosides” NUCLEOSIDES & NUCLEOTIDES , 12(7), 687-99 CODEN: NUNUD5; ISSN: 0732-8311, 1993, XP008091463 |
| 2 | * | See also references of WO2006073197A1 |
| EP2419097A1 * | Apr 16, 2010 | Feb 22, 2012 | Taisho Pharmaceutical Co., Ltd. | Pharmaceutical compositions |
| EP2455374A1 * | Oct 15, 2009 | May 23, 2012 | Janssen Pharmaceutica N.V. | Process for the Preparation of Compounds useful as inhibitors of SGLT |
| EP2601949A2 * | Apr 16, 2010 | Jun 12, 2013 | Taisho Pharmaceutical Co., Ltd. | Pharmaceutical compositions |
| EP2668953A1 * | May 15, 2009 | Dec 4, 2013 | Bristol-Myers Squibb Company | Pharmaceutical compositions comprising an SGLT2 inhibitor with a supply of carbohydrate and/or an inhibitor of uric acid synthesis |
| WO2009143020A1 | May 15, 2009 | Nov 26, 2009 | Bristol-Myers Squibb Company | Method for treating hyperuricemia employing an sglt2 inhibitor and composition containing same |
| WO2010043682A2 * | Oct 15, 2009 | Apr 22, 2010 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of sglt |
| WO2010119990A1 | Apr 16, 2010 | Oct 21, 2010 | Taisho Pharmaceutical Co., Ltd. | Pharmaceutical compositions |
| WO2013152654A1 * | Mar 14, 2013 | Oct 17, 2013 | Theracos, Inc. | Process for preparation of benzylbenzene sodium-dependent glucose cotransporter 2 (sglt2) inhibitors |
-
Luseogliflozin: Phase III data 10/21/2013
Week in Review, Clinical ResultsTaisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Molecular target: Sodium-glucose cotransporter 2 (SGLT2) Description: Oral sodium-glucose… -
Luseogliflozin: Phase III data 10/21/2013
Week in Review, Clinical ResultsTaisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Molecular target: Sodium-glucose cotransporter 2 (SGLT2) Description: Oral sodium-glucose… -
Luseogliflozin regulatory update 05/13/2013
Week in Review, RegulatoryTaisho Pharmaceutical Holdings Co. Ltd. (Tokyo:4581), Tokyo, Japan Product: Luseogliflozin (TS-071) Business: Endocrine/Metabolic Last month, Taisho’s Taisho Pharmaceutical Co. Ltd. subsidiary submitted a regulatory … -
Strategy: Doubling down in diabetes 05/06/2013
Merck shoring up slowing diabetes franchise with Pfizer, Abide dealsBioCentury on BioBusiness, StrategyAs sales flatten for Merck’s sitagliptin franchise and a new class of oral diabetes drugs comes to market, the pharma has tapped Pfizer and Abide to shore up its position.
see
SEE
http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-132352
RedHill Biopharma Ltd. Acquires Phase 2 Oncology Drug Upamostat MESUPRON From Wilex AG
Upamostat
CAS: 590368-25-5
Chemical Formula: C32H47N5O6S
Exact Mass: 629.32470
Synonym: WX 671; WX-671; WX671. Upamostat; Brand name: Mesupron.
IUPAC/Chemical name:
(S)-ethyl 4-(3-(3-(N-hydroxycarbamimidoyl)phenyl)-2-(2,4,6-triisopropylphenylsulfonamido)propanoyl)piperazine-1-carboxylate
RedHill Biopharma Ltd. , an Israeli biopharmaceutical company focused on late clinical-stage drugs for inflammatory and gastrointestinal diseases, including cancer, and WILEX AG , a biopharmaceutical company focused on oncology, based in Munich, Germany, today announced that they have signed an exclusive license agreement for the oncology drug … (more)
Upamostat, also known as Mesupron, WX-671, is an orally bioavailable, 3-amidinophenylalanine-derived, second generation serine protease inhibitor prodrug targeting the human urokinase plasminogen activator (uPA) system with potential antineoplastic and antimetastatic activities. After oral administration, serine protease inhibitor WX-671 is converted to the active Nα-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenyla lanine-4-ethoxycarbonylpiperazide (WX-UK1), which inhibits several serine proteases, particularly uPA; inhibition of uPA may result in the inhibition of tumor growth and metastasis. uPA is a serine protease involved in degradation of the extracellular matrix and tumor cell migration and proliferation.
|
Information about this agent |
WX-671 (Mesupron) is an orally available prodrug of WX-UK1, a serine protease inhibitor that inhibits uPA as well as other serine proteases. WX-UK1 (Setyono-Han et al., Thromb Haemost 2005) and WX-671 have shown to efficiently reduce primary tumor growth and metastasis formation in a variety of animal models. The proteolytic factor uPA and its inhibitor PAI-1 belong to those biological factors which have provided the highest level of evidence (LOE1) in terms of their prognostic and predictive significance. WX-671 is currently the only drug in Phase II aiming at this target.Results: All 95 patients were accrued between Jun 2007 and Aug 2008. Efficacy is assessed by a central reader at regular intervals based on digital CT images. By end of 2009, 2 patients were still on treatment without signs of progression, 64 patients had died. Preliminary analysis of overall survival showed an increase in overall survival from 10.2 mo (gemcitabine alone) to 13.5 mo for the combination of gemcitabine and WX-671. 1-year survival increased from 37% with gemcitabine to 53% when combined with 400 mg WX- 671. Conclusions: The combination of daily oral WX-671 in combination with weekly i.v. gemcitabine was well tolerated. see asco.com’s website.
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References |
1. Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes) By Kotthaus, Joscha; Steinmetzer, Torsten; van de Locht, Andreas; Clement, Bernd From Journal of Enzyme Inhibition and Medicinal Chemistry (2011), 26(1), 115-122.
2. Combined treatment of cancer by urokinase inhibition and a cytostatic anti-cancer agent for enhancing the anti-metastatic effect By Schmalix, Wolfgang; Schneider, Anneliese; Setyono-Han, Buddy; Foekens, Johannes From U.S. Pat. Appl. Publ. (2008), US 20080226624 A1 20080918.
3. Peptides and small molecules targeting the plasminogen activation system: towards prophylactic anti-metastasis drugs for breast cancer By Tyndall, Joel D. A.; Kelso, Michael J.; Clingan, Phillip; Ranson, Marie From Recent Patents on Anti-Cancer Drug Discovery (2008), 3(1), 1-13.
4. Synthesis of hydroxyamidine and hydroxyguanidine amino acid or oligopeptide derivatives for use as urokinase plasminogen activator inhibitors for the treatment of cancer and its metastasis By Sperl, Stefan; Buergle, Markus; Schmalix, Wolfgang; Wosikowski, Katja; Clement, Bernd From U.S. Pat. Appl. Publ. (2006), US 20060142305 A1 20060629.
5. Crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or its salts By Grunenberg, Alfons; Lenz, Jana From PCT Int. Appl. (2006), WO 2006056448 A1 20060601.
6. Synthesis of hydroxyamidine and hydroxyguanidine amino acid or oligopeptide derivatives for use as urokinase plasminogen activator inhibitors for the treatment of cancer and its metastasis By Sperl, Stefan; Burgle, Markus; Schmalix, Wolfgang; Wosikowski, Katja; Clement, Bernd From PCT Int. Appl. (2004), WO 2004103984 A1 20041202.
7. Preparation of 3-amidinophenylalanine derivatives from 3-cyanophenylalanines via reduction and hydrogenation under mild conditions By Ziegler, Hugo; Wikstroem, Peter From PCT Int. Appl. (2003), WO 2003072559 A1 20030904.
1. Buddy et al, Suppression of Rat Brest Cancer Metastasis and Reduction of Primary Tumor Growth by the Small Synthetic Urokinase Inhibitor WX-UK1. Thromb Haemost. 2005, 93:779-786.
2. Ertongur S, Lang S, Mack B, Wosikowski K, Muehlenweg B, Gires O. Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system. Int J Cancer. 2004, 110(6):815-24.
3. Setyono-Han B, Stürzebecher J, Schmalix WA, Muehlenweg B, Sieuwerts AM, Timmermans M, Magdolen V, Schmitt M, Klijn JG, Foekens JA. Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1. Thromb Haemost. 2005, 93(4):779-86.
FDA grants orphan drug designation to Insys Therapeutics’ pharmaceutical cannabidiol
| Systematic (IUPAC) name | |
|---|---|
| 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol | |
| Clinical data | |
| Trade names | Epidiolex |
| AHFS/Drugs.com | International Drug Names |
| Legal status | Schedule I (US)Schedule II (Can)(THC – Schedule/Level I; THC and CBD two main chemicals in cannabis) |
| Pharmacokinetic data | |
| Bioavailability | 13-19% (oral),[1] 11-45% (mean 31%; inhaled)[2] |
| Half-life | 9 h[1] |
| Identifiers | |
| CAS number | 13956-29-1 |
| ATC code | None |
| PubChem | CID 644019 |
| ChemSpider | 24593618 |
| UNII | 19GBJ60SN5 |
| Chemical data | |
| Formula | C21H30O2 |
| Mol. mass | 314.4636 |
| Physical data | |
| Melt. point | 66 °C (151 °F) |
| Boiling point | 180 °C (356 °F) (range: 160–180 °C)[3] |
FDA grants orphan drug designation to Insys Therapeutics’ pharmaceutical cannabidiol – Pharmaceutical Technology
US-based specialty pharmaceutical company Insys Therapeutics has obtained orphan drug designation from the US Food and Drug Administration (FDA) for its pharmaceutical cannabidiol for treatment of Lennox-Gastaut Syndrome.
Insys Therapeutics president and CEO Michael Babich said: “With no cure and persistence of seizures with current antiepileptic medications, the orphan drug designation recognises the significant, unmet need that exists among children with this severe form of epilepsy and the teams who provide their care.
“We have the unique opportunity to test a controlled pharmaceutical CBD product for Lennox-Gastaut Syndrome, and our company is committed to advancing cannabinoid therapies that have the potential to provide significant medical benefits to patients across multiple indications.
“With no cure and persistence of seizures with current antiepileptic medications, the orphan drug designation recognises the significant, unmet need that exists among children with this severe form of epilepsy and the teams who provide their care.”
“We expect to file an investigational new drug application (IND) for CBD in the second half of 2014.”
Cannabidiol (CBD) is one of at least 60 active cannabinoids identified in cannabis.[4] It is a major phytocannabinoid, accounting for up to 40% of the plant’s extract.[5] CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol(THC).[5] An orally-administered liquid containing CBD has received orphan drug status in the US, for use as a treatment for dravet syndrome under the brand name, Epidiolex.[6]
Clinical applications
The bud of a Cannabis sativa flower coated with trichomes
Antimicrobial actions
CBD absorbed transcutaneously may attenuate the increased sebum production at the root of acne, according to an untested hypothesis.[7]
Neurological effects
A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of CBD. The researchers attributed this attenuation of memory effects to CBD’s role as a CB1 antagonist. Transdermal CBD is neuroprotective in animals.[8]
Cannabidiol’s strong antioxidant properties have been shown to play a role in the compound’s neuroprotective and anti-ischemiceffects.[9]
- Parkinson’s disease
It has been proposed that CBD may help people with Parkinson’s disease, but promising results in animal experiments were not confirmed when CBD was trialled in humans.[10]
Psychotropic effect
CBD has anti-psychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latentschizophrenia;[5] some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated.[11] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.[11][12] Leweke et al. performed a double blind, 4 week, explorative controlled clinical trial to compare the effects of purified cannabidiol and the atypical antipsychoticamisulpride on improving the symptoms of schizophrenia in 42 patients with acute paranoid schizophrenia. Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric Rating Scale andPositive and Negative Syndrome Scale. While there was no statistical difference between the two treatment groups, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.[13]
Studies have shown cannabidiol decreases activity of the limbic system[14] and decreases social isolation induced by THC.[15] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[16][17] However, chronic cannabidiol administration in rats was recently found to produce anxiogenic-like effects, indicating that prolonged treatment with cannabidiol might incite anxiogenic effects.[18]
Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.[19][20][21]
Cancer
The American Cancer Society says: “There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer.”[22] Laboratory experiments have been performed on the potential use of cannabinoids for cancer therapy but as of 2013 results have been contradictory and knowledge remains poor.[23] Cannabinoids have been recommended for cancer pain but the adverse effects may make them a less than ideal treatment; two cannabinoid-based medicines have been approved as a backup remedy for nausea associated withchemotherapy.[4]
Dravet syndrome
See also: Charlotte’s Web (cannabis)
Dravet syndrome is a rare form of epilepsy that is difficult to treat. Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the second year of life other seizure types begin to emerge.[24] While high profile and anecdotal reports have sparked interest in treatment with cannabinoids,[25] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[25][26]
CBD-enhanced cannabis
Decades ago, selective breeding by growers in US dramatically lowered the CBD content of cannabis; their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[27] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.[28]
In November 2012, Tikun Olam, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[29][30] The researchers said the cannabis plant, enriched with CBD, “can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes”. Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said “…Avidekel is thought to be the first CBD-enriched cannabis plant with no THC to have been developed in Israel”.[31]
Pharmacology
Pharmacodynamics
Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[9] While one would assume that this would cause cannabidiol to reduce the effects of THC, it may potentiate THC’s effects by increasing CB1 receptor density or through another CB1-related mechanism.[32] It is also an inverse agonist of CB2receptors.[9][33] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[34]Cannabidiol has also been shown to act as a 5-HT1A receptor agonist,[35] an action which is involved in its antidepressant,[19][36] anxiolytic,[36][37] and neuroprotective[38][39]effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.[40] Cannabidiol’s pharmacologial effects have also been attributed to PPAR-γ receptor agonism andintracellular calcium release.[5]
Pharmacokinetic interactions
There is some preclinical evidence to suggest that cannabidiol may reduce THC clearance, modestly increasing THC’s plasma concentrations resulting in a greater amount of THC available to receptors, increasing the effect of THC in a dose-dependent manner.[41][42] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[43]
Pharmaceutical preparations
Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC. The drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis.[44][45][46]
Isomerism
| 7 double bond isomers and their 30 stereoisomers | ||||||||
|---|---|---|---|---|---|---|---|---|
| Formal numbering | Terpenoid numbering | Number of stereoisomers | Natural occurrence | Convention on Psychotropic SubstancesSchedule | Structure | |||
| Short name | Chiral centers | Full name | Short name | Chiral centers | ||||
| Δ5-cannabidiol | 1 and 3 | 2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol | Δ4-cannabidiol | 1 and 3 | 4 | No | unscheduled | -5-pentyl-1,3-benzenediol.png) |
| Δ4-cannabidiol | 1, 3 and 6 | 2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol | Δ5-cannabidiol | 1, 3 and 4 | 8 | No | unscheduled | -5-pentyl-1,3-benzenediol.png) |
| Δ3-cannabidiol | 1 and 6 | 2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol | Δ6-cannabidiol | 3 and 4 | 4 | ? | unscheduled | -5-pentyl-1,3-benzenediol.png) |
| Δ3,7-cannabidiol | 1 and 6 | 2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol | Δ1,7-cannabidiol | 3 and 4 | 4 | No | unscheduled | -5-pentyl-1,3-benzenediol.png) |
| Δ2-cannabidiol | 1 and 6 | 2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol | Δ1-cannabidiol | 3 and 4 | 4 | Yes | unscheduled | -5-pentyl-1,3-benzenediol.png) |
| Δ1-cannabidiol | 3 and 6 | 2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol | Δ2-cannabidiol | 1 and 4 | 4 | No | unscheduled | -5-pentyl-1,3-benzenediol.png) |
| Δ6-cannabidiol | 3 | 2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol | Δ3-cannabidiol | 1 | 2 | No | unscheduled | -5-pentyl-1,3-benzenediol.png) |
See also: Tetrahydrocannabinol#Isomerism, Abnormal cannabidiol.
Chemistry
Cannabidiol is insoluble in water but soluble in organic solvents, such as pentane. At room temperature it is a colorless crystalline solid.[47] In strongly basic medium and the presence of air it is oxidized to a quinone.[48] Under acidic conditions it cyclizes to THC.[49] The synthesis of cannabidiol has been accomplished by several research groups.[50][51][52]
http://pubs.rsc.org/en/content/articlelanding/2005/ob/b416943c#!divAbstract
https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1964-01-01_4_page005.html
http://pubs.rsc.org/en/content/articlelanding/2005/ob/b416943c#!divAbstract
Biosynthesis
Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the last step, where CBDA synthase performs catalysis instead of THCA synthase.[53]
Legal status
Cannabidiol is not scheduled by the Convention on Psychotropic Substances.
Cannabidiol is a Schedule II drug in Canada.[54]
Cannabidiol’s legal status in the United States:
The DEA Drug Schedule classifies synthetic THC (Tetrahydrocannabinol) as a schedule III substance (eg Marinol); while the natural marijuana plant is listed as Schedule I. Cannabidiol is not named specifically on the list.[55] However the CSA does mention all natural Phytocannabinoids in Schedule 1 Code 7372, which would include CBD.[55]
Marijuana (along with all of its cannabinoids) is defined by 21 U.S.C. §802(16), which is part of the Controlled Substances Act.[56][57][58] There is an exemption for certain Hemp products produced abroad. Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year. Hemp finished products which meet the specific definitions including hemp oil which may contain cannabidiol are legal in the United States but aren’t used for getting high.[59]
Some cannabidiol oil is derived from marijuana and therefore contains higher levels of THC.[60] This type of cannabidiol oil would be considered a Schedule I as a result of the THC present.[60]
US patent
In October 2003, U.S. patent #6630507 entitled “Cannabinoids as antioxidants and neuroprotectants” was assigned to “The United States Of America As Represented By The Department Of Health And Human Services.” The patent was filed in April 1999 and listed as the inventors: Aidan J. Hampson, Julius Axelrod, and Maurizio Grimaldi, who all held positions at the National Institute of Mental Health (NIMH) in Bethesda, MD, which is part of the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). The patent mentions cannabidiol’s ability as an antiepileptic, to lower intraocular pressure in the treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties, its ability to prevent neurotoxicity mediated by NMDA, AMPA, or kainate receptors; its ability to attenuate glutamate toxicity, its ability to protect against cellular damage, its ability to protect brains from ischemic damage, its anxiolytic effect, and its superior antioxidant activity which can be used in the prophylaxis and treatment of oxidation associated diseases.[61]
| “ | “Oxidative associated diseases include, without limitation, free radical associated diseases, such as ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents (such as a thromboembolic or hemorrhagic stroke) that can lead to ischemia or an infarct in the brain, operative ischemia, traumatic hemorrhage (for example a hypovolemic stroke that can lead to CNS hypoxia or anoxia), spinal cord trauma, Down’s syndrome, Crohn’s disease, autoimmune diseases (e.g. rheumatoid arthritis or diabetes), cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellular apoptosis, radiation sickness, and others. The present invention is believed to be particularly beneficial in the treatment of oxidative associated diseases of the CNS, because of the ability of the cannabinoids to cross the blood brain barrier and exert their antioxidant effects in the brain. In particular embodiments, the pharmaceutical composition of the present invention is used for preventing, arresting, or treating neurological damage in Parkinson’s disease, Alzheimer’s disease and HIV dementia; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest or cardiac arrest, and anoxia caused by drowning, brain surgery or trauma (such as concussion or spinal cord shock).”[61] | ” |
On November 17, 2011, the Federal Register published that the National Institutes of Health of the United States Department of Health and Human Services was “contemplating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507” to the company KannaLife based in New York, for the development and sale of cannabinoid and cannabidiol based therapeutics for the treatment of hepatic encephalopathy in humans.[62][63][64]
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- ^ Jump up to:a b Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (January 2009). “5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats”. British Journal of Pharmacology 156 (1): 181–8. doi:10.1111/j.1476-5381.2008.00046.x.PMC 2697769. PMID 19133999.
- Jump up^ Campos AC, Guimarães FS (August 2008). “Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x.PMID 18446323.
- Jump up^ Mishima K, Hayakawa K, Abe K, et al. (May 2005). “Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism”.Stroke; a Journal of Cerebral Circulation 36 (5): 1077–82.doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890.
- Jump up^ Hayakawa K, Mishima K, Nozako M, et al. (March 2007). “Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance”. Neuropharmacology 52 (4): 1079–87.doi:10.1016/j.neuropharm.2006.11.005. PMID 17320118.
- Jump up^ Kathmann, Markus; Flau, Karsten; Redmer, Agnes; Tränkle, Christian; Schlicker, Eberhard (2006). “Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors”. Naunyn-Schmiedeberg’s Archives of Pharmacology 372 (5): 354–361.doi:10.1007/s00210-006-0033-x. PMID 16489449.
- Jump up^ Bornheim, LM; Kim, KY; Li, J; Perotti, BY; Benet, LZ (August 1995). “Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain”. Drug Metabolism and Disposition 23 (8): 825–831. PMID 7493549.
- Jump up^ Klein, C; Karanges, E; Spiro, A; Wong, A; Spencer, J; Huynh, T; Gunasekaran, N; Karl, T; Long, LE; Huang, XF; Liu, K; Arnold, JC; McGregor, IS (November 2011). “Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats”.Psychopharmacology 218 (2): 443–457. doi:10.1007/s00213-011-2342-0.PMID 21667074.
- Jump up^ Hunt, CA; Jones, RT; Herning, RI; Bachman, J (June 1981). “Evidence that Cannabidiol Does Not Significantly Alter the Pharmacokinetics of Tetrahydrocannabinol in Man”.Journal of Pharmacokinetics and Biopharmaceutics 9 (3): 245–260.doi:10.1007/BF01059266. PMID 6270295.
- Jump up^ United States Adopted Names Council: Statement on a nonproprietary name
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- Jump up^ GWPharma- Welcome
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- Mechoulam R, Ben-Zvi Z (1968). “Hashish—XIII On the nature of the beam test”.Tetrahedron 24 (16): 5615–5624. doi:10.1016/0040-4020(68)88159-1. PMID 5732891.
- Gaoni Y, Mechoulam R (1966). “Hashish—VII The isomerization of cannabidiol to tetrahydrocannabinols”. Tetrahedron 22 (4): 1481–1488. doi:10.1016/S0040-4020(01)99446-3.
- Petrzilka T, Haefliger W, Sikemeier C, Ohloff G, Eschenmoser A (1967). “Synthese und Chiralität des (-)-Cannabidiols”. Helv. Chim. Acta 50 (2): 719–723.doi:10.1002/hlca.19670500235. PMID 5587099.
- Gaoni Y, Mechoulam R (1985). “Boron trifluoride etherate on alumuna – a modified Lewis acid reagent. An improved synthesis of cannabidiol”. Tetrahedron Letters 26 (8): 1083–1086. doi:10.1016/S0040-4039(00)98518-6.
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- Marks, M.; Tian, L.; Wenger, J.; Omburo, S.; Soto-Fuentes, W.; He, J.; Gang, D.; Weiblen, G.; Dixon, R. (2009). “Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa”. Journal of Experimental Botany60 (13): 3715–3726. doi:10.1093/jxb/erp210. PMC 2736886. PMID 19581347.
- Controlled Drugs and Substances Act – Schedule II
- CSA Schedule, List of drugs by schedule.
- Definition of marijuana under the Controlled Substances Act.
- Title 21 US Code Controlled Substances Act, text of the CSA.
- Hemp Industries Assn., v. Drug Enforcement Admin., 9th Circuit Court of Appeals case involving industrial hemp.
- Hemp, Many definitions of common terms associated with hemp, including the history of hemp use.
- Cannabidiol: The side of marijuana you don’t know
- US patent 6630507, Hampson, Aidan J.; Axelrod, Julius; Grimaldi, Maurizio, “Cannabinoids as antioxidants and neuroprotectants”, issued 2003-10-07
- “Federal Register | Prospective Grant of Exclusive License: Development of Cannabinoid(s) and Cannabidiol(s) Based Therapeutics To Treat Hepatic Encephalopathy in Humans”. Federalregister.gov. November 17, 2011. Retrieved August 13, 2013.
- “KannaLife Sciences, Inc. Signs Exclusive License Agreement With National Institutes Of Health Office Of Technology Transfer (NIH-OTT)”. thestreet.com. Retrieved 2012-07-09.
- “KannaLife in R&D Collaboration for Cannabinoid-Based Drugs”. Genengnews.com. Retrieved 2013-04-04.
External links
- Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.
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LONDON, Nov. 15, 2013
GW Pharmaceuticals plc (AIM: GWP, Nasdaq: GWPH, “GW”) announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for Epidiolex(R), our product candidate that contains plant-derived Cannabidiol (CBD) as its active ingredient, for use in treating children with Dravet syndrome, a rare and severe form of infantile-onset, genetic, drug-resistant epilepsy syndrome. Epidiolex is an oral liquid formulation of a highly purified extract of CBD, a non-psychoactive molecule from the cannabis plant. Following receipt of this orphan designation, GW anticipates holding a pre-IND meeting with the FDA in the near future to discuss a development plan for Epidiolex in Dravet syndrome.
Dravet syndrome is a rare pediatric epilepsy syndrome with a distinctive but complex electroclinical presentation. Onset of Dravet syndrome occurs during the first year of life with clonic and tonic-clonic seizures in previously healthy and developmentally normal infants. Prognosis is poor and patients typically develop intellectual disability and life-long ongoing seizures. There are approximately 5,440 patients with Dravet in the United States and an estimated 6,710 Dravet patients in Europe. These figures may be an underestimate as this syndrome is reportedly underdiagnosed.
In addition to GW’s clinical development program for Epidiolex in Dravet syndrome, which is expected to commence in 2014, GW has also made arrangements to enable independent U.S. pediatric epilepsy specialists to treat high need pediatric epilepsy cases with Epidiolex immediately. To date in 2013, a total of seven “expanded access” INDs have been granted by the FDA to U.S. clinicians to allow treatment with Epidiolex of approximately 125 children with epilepsy. These children suffer from Dravet syndrome, Lennox-Gastaut syndrome, and other pediatric epilepsy syndromes. GW is aware of further interest from additional U.S. and ex-U.S. physicians to host similar INDs for Epidiolex. GW expects data generated under these INDs to provide useful observational data during 2014 on the effect of Epidiolex in the treatment of a range of pediatric epilepsy syndromes.
“I, together with many colleagues in the U.S. who specialize in the treatment of childhood epilepsy, very much welcome the opportunity to investigate Epidiolex in the treatment of Dravet syndrome. The FDA’s timely approval of the orphan drug designation for Epidiolex in Dravet syndrome is a key milestone that comes after many years of reported clinical cases that suggest encouraging evidence of efficacy for CBD in this intractable condition,” stated Dr. Orrin Devinsky, Professor of Neurology, Neurosurgery and Psychiatry in New York City. “With GW now making plans to advance Epidiolex through an FDA development program, we have the prospect for the first time of fully understanding the science of CBD in epilepsy with a view to making an appropriately tested and approved prescription medicine available in the future for children who suffer from this debilitating disease.”
“GW is proud to be at the forefront of this important new program to treat children with Dravet Syndrome and potentially other forms of intractable childhood epilepsy. For families in these circumstances, their lives are significantly impacted by constant and often times very severe seizures in children where all options to control these seizures have been exhausted,” stated Dr. Stephen Wright, GW’s R&D Director. “GW intends to advance a full clinical development program for Epidiolex in Dravet syndrome as quickly as possible, whilst at the same time helping families in the short term through supporting physician-led INDs to treat intractable cases. Through its efforts, GW aims to provide the necessary evidence to confirm the promise of CBD in epilepsy and ultimately enabling children to have access to an FDA-approved prescription CBD medicine.”
“This orphan program for Epidiolex in childhood epilepsy is an important corporate strategic priority for GW. Following receipt of today’s orphan designation, GW now intends to commence discussions with the FDA regarding the U.S. regulatory pathway for Epidiolex,” stated Justin Gover, GW’s Chief Executive Officer. “GW intends to pursue this development in-house and retains full commercial rights to Epidiolex.”
About Orphan Drug Designation
Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition — generally a disease or condition that affects fewer than 200,000 individuals in the U.S. The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the U.S. for that product, for that indication.
About GW Pharmaceuticals plc
Founded in 1998, GW is a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform in a broad range of disease areas. GW commercialized the world’s first plant-derived cannabinoid prescription drug, Sativex(R), which is approved for the treatment of spasticity due to multiple sclerosis in 22 countries. Sativex is also in Phase 3 clinical development as a potential treatment of pain in people with advanced cancer. This Phase 3 program is intended to support the submission of a New Drug Application for Sativex in cancer pain with the U.S. Food and Drug Administration and in other markets around the world. GW has established a world leading position in the development of plant-derived cannabinoid therapeutics and has a deep pipeline of additional clinical-stage cannabinoid product candidates targeting epilepsy (including an orphan pediatric epilepsy program), Type 2 diabetes, ulcerative colitis, glioma and schizophrenia. For further information, please visit http://www.gwpharm.com.
Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.It is a major constituent of the plant, second totetrahydrocannabinol (THC), and represents up to 40% in its extracts. Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC, including to epilepsy, multiple sclerosis spasms, anxiety disorders, bipolar disorder,schizophrenia,nausea, convulsion and inflammation, as well as inhibiting cancer cell growth. There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.Cannabidiol has displayed sedative effects in animal tests. Other research indicates that CBD increases alertness. CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.
PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF)
ATALUREN
PTC 124
3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
| MF C15H9FN2O3 | ||
| Molecular Weight | 284.24 | |
| CAS Registry Number | 775304-57-9 |
PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF) – MarketWatch
Ataluren, formerly known as PTC124, is a small-molecular agent designed by PTC Therapeutics and sold under the trade nameTranslarna. It makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. There is ongoing debate over whether Ataluren is truly a functional drug (inducing codon read-through), or if it is nonfunctional, and the result was a false-positive hit from a biochemical screen based on luciferase.[1]
Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,[2][3] such as some people with cystic fibrosis and Duchenne muscular dystrophy. In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.[4] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug. However, other phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.[5] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.[6]
In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.[7]
Ataluren appears to be most effective for the stop codon ‘UGA’.[2]
On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).[8]
It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).
References
- Derek (2013-09-18). “The Arguing Over PTC124 and Duchenne Muscular Dystrophy. In the Pipeline:”. Pipeline.corante.com. Retrieved 2013-11-28.
- Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (May 2007). “PTC124 targets genetic disorders caused by nonsense mutations”. Nature 447 (7140): 87–91.doi:10.1038/nature05756. PMID 17450125.
- Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (Apr 2007). “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers”. Journal of clinical pharmacology 47 (4): 430–444. doi:10.1177/0091270006297140. PMID 17389552.
- “PTC THERAPEUTICS AND GENZYME CORPORATION ANNOUNCE PRELIMINARY RESULTS FROM THE PHASE 2B CLINICAL TRIAL OF ATALUREN FOR NONSENSE MUTATION DUCHENNE/BECKER MUSCULAR DYSTROPHY (NASDAQ:PTCT)”. Ptct.client.shareholder.com. Retrieved 2013-11-28.
- Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910. PMID 21233271. Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (November 2010). “Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis”. American Journal of Respiratory and Critical Care Medicine 182 (10): 1262–1272.doi:10.1164/rccm.201001-0137OC. PMID 20622033.
- “PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)”. Ptct.client.shareholder.com. 2010-12-21. Retrieved 2013-11-28.
- Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115.
- http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23
External links
other sources
rINN: Ataluren
Other Names
PTC124®, 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
Pharmacological Information
Pharmacology Images
Ataluren Molecule
Web information on Ataluren
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature
Orphan drug under investigation for treatment of genetic conditions where nonsense mutations result in premature termination of polypeptides. This drug, which is convenient to deliver orally, appears to allow ribosomal transcription ofRNA to continue past premature termination codon mutations with correct reading of the full normal transcript which then terminates at the proper stop codon. Problematically it has been postulated that assay artifact may have complicated evaluation of its efficacy which appears to be less than gentamicin.[1] Faults of this class in the transcription process are involved in several inherited diseases.
Some forms of cystic fibrosis and Duchenne muscular dystrophy are being targeted in the development stage of the drug.[2] Phase I and II trials are promising for cystic fibrosis.[3][4] In a mouse model of Duchenne muscular dystrophy, restoration of muscle function occurred.[5]
A potential issue is that there may be parts of the human genome whose optimal gene function through evolution has resulted from relatively recent in evolutionary terms insertion of a premature termination codon and so functional suboptimal transcripts of other proteins or functional RNAs might result.
References
- ↑ Roberts RG. A read-through drug put through its paces. PLoS biology. 2013; 11(6):e1001458.(Link to article – subscription may be required.)
- ↑ Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. Journal of clinical pharmacology. 2007 Apr; 47(4):430-44.(Link to article– subscription may be required.)
- ↑ Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008 Aug 30; 372(9640):719-27.(Link to article – subscription may be required.)
- ↑ Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL. Ataluren (PTC124) Induces Cystic Fibrosis Transmembrane Conductance Regulator Protein Expression and Activity in Children with Nonsense Mutation Cystic Fibrosis. American journal of respiratory and critical care medicine. 2010 Nov 15; 182(10):1262-72.(Link to article – subscription may be required.)
- ↑ Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3; 447(7140):87-91.(Link to article – subscription may be required.)
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A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.
The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation — also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.
Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.
The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.
PTC124 has been developed by PTC Therapeutics.
It may take guts to cure diabetes: Human GI cells retrained to produce insulin
By switching off a single gene, scientists at Columbia University’s Naomi Berrie Diabetes Center have converted human gastrointestinal cells into insulin-producing cells, demonstrating in principle that a drug could retrain cells inside a person’s GI tract to produce insulin.
The new research was reported today in the online issue of the journal Nature Communications.
“People have been talking about turning one cell into another for a long time, but until now we hadn’t gotten to the point of creating a fully functional insulin-producing cell by the manipulation of a single target,” said the study’s senior author, Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes (in Medicine) at Columbia University Medical Center (CUMC).
The finding raises the possibility that cells lost in type 1 diabetes may be more easily replaced through the reeducation of existing cells than through the transplantation of new cells created from embryonic or adult…
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Artificial enzyme mimics the natural detoxification mechanism in liver cells
Mode of action of molybdenum oxide nanoparticles: (a) treatment of sulfite oxidase deficient liver cells; (b) mitochondria are directly targeted, nanoparticles accumulate in proximity to the membrane; (c) sulfite is oxidized to cellular innocuous sulfate.
Scientists at Johannes Gutenberg University Mainz in Germany have discovered that molybdenum trioxide nanoparticles oxidize sulfite to sulfate in liver cells in analogy to the enzyme sulfite oxidase. The functionalized Molybdenum trioxide nanoparticles can cross the cellular membrane and accumulate at the mitochondria, where they can recover the activity of sulfite oxidase.
Sulfite oxidase is a molybdenum containing enzyme located in the mitochondria of liver and kidney cells, which catalyzes the oxidation of sulfite to sulfate during the protein and lipid metabolism and therefore plays an important role in cellular detoxification processes. A lack of functional sulfite oxidase is a rare but fatal genetic disease causing neurological disorders, mental retardation, physical deformities as well as…
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A Recipe To Make Cannabis Oil For A Chemotherapy Alternative
Awareness with regards to cannabis as a treatment and potential cure for cancer has been rapidly increasing over the past few years. Several studies over the last decade have clearly (without question) demonstrated the anti-tumoral effects of the plant. Cannabinoids (any group of related compounds that include cannabinol and the active constituents of cannabis) activate cannabinoid receptors in the body. The human body itself produces compounds called endocannabinoids and they play a very important role in many processes within the body to help create a healthy environment.
Since radiation and chemotherapy are the only two approved treatments for cancer, it’s important to let people know that other options do exist. There’s nothing wrong with exploring these options and finding out more information about them so people can make the best possible choice for themselves. It’s always important to do your own research.
A number of people have used this treatment…
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DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
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New Drug Approvals 