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Menarini launches premature ejaculation drug in Singapore
DAPOXETINE
Menarini has launched dapoxetine for premature ejaculation in Singapore, having recently published a survey highlighting the rising problem of sexual dissatisfaction in the Asia-Pacific region.
The Italian drugmaker acquired Priligy (dapoxetine)from Johnson & Johnson last year and the drug is now approved in over 50 countries. It estimates that PE affects 34% of men in Singapore at some point in their lives.
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Dapoxetine, marketed as Priligy (among and other brands) is the first compound developed specially for the treatment of premature ejaculation (PE) in men 18–64 years old.Dapoxetine works by inhibiting the serotonin transporter, increasing serotonin’s action at the post synaptic cleft, and as a consequence promoting ejaculatory delay. As a member of selective serotonin reuptake inhibitor (SSRI) family, dapoxetine was initially created as an antidepressant. However, unlike other SSRIs, dapoxetine is absorbed and eliminated rapidly in the body. Its fast acting property makes it suitable for the treatment of PE but not as an antidepressant.[3]
Originally created by Eli Lilly pharmaceutical company, dapoxetine was sold to Johnson & Johnson in 2003 and submitted as a new drug application to the Food and Drug Administration (FDA) for the treatment of PE in 2004. Dapoxetine has been sold in several European and Asian countries, and lately in Mexico. In the US, dapoxetine is in phase III development and expected to be marketed soon. In 2012, Menarini acquired the rights to commercialise Priligy in Europe, most of Asia, Africa, Latin America and the Middle East.
Premature ejaculation
Randomized, double blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for the treatment of PE. Different dosage has different impacts on different type of PE. Dapoxetine 60 mg significantly improves the mean intravaginal ejaculation latency time (IELT) compare to that of dapoxetine 30 mg in men with lifelong PE, but there is no different in men with acquired PE. Dapoxetine, given 1–3 hours before sexual episode, prolongs IELT, increases the sense of control and sexual satisfaction in men of 18 to 64 years of age with PE. Since PE is associated with personal distress, interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition.Because lack of specific approval treatment for PE in the US and some other countries, other SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram have been used as off label drugs to treat PE. Waldinger’s meta analysis shows that the use of these conventional antidepressants increasing IELT from two to ninefold above base line in comparison of three to eightfold when dapoxetine is used. However, these SSRIs must be taken daily in order to achieve meaningful efficacy, and the long half-life increases the risk of the drug accumulation and as a consequence increased of adverse effects such as decreasing sexual libido and causing erectile dysfunction. Dapoxetine, on the other hand, is a fast-acting SSRI. It is rapidly absorbed and eliminated from the body within a few hours. This favorable pharmacokinetics minimizes the risk of the drug’s accumulation in the body, and therefore reducing side effects.
African medicine-cyclotides as an aid during child birth
 |
| Oldenlandia affinis was used by native women in the Zaire as an aid during childbirth. A tea was made of the leaves and imbibed during labour. |
Cyclotides are plant-derived peptides of approximately 30 amino acids. They have the characteristic structural features of a head-to-tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. Their unique structural features lead to exceptional stability. This and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications.
David J Craik, University of Queensland, Brisbane, Australia, whose laboratory is working over 20 years in the field, summarizes the history of cyclotides
http://www.chemistryviews.org/details/news/5012211/History_of_Cyclotides.html
more info on cyclotides
This is how it was discovered: a physician working in the Democratic Republic of Congo noticed that laboring women were drinking tea made from Oleanda affinis to induce childbirth. Theactive ingredient was the first cyclotide to be discovered. Since then, cyclotides have been shown to be antibiotic, antiviral and insecticidal.
Figure 1. Structure and sequence of the prototypic cyclotide kalata B1
Cyclotides are small disulfide-rich proteins that have the unusual feature of a cyclic backbone (hence the name cyclo – peptides). They contain six conserved cystine residues that are arranged in a cystine knot topology in which two disulfide bonds and their connecting backbone segments form an embedded ring in the structure that is penetrated by a third disulfide bond, as shown below.
Cyclotides have a range of interesting biological activities including anti-HIV and neurotensin inhibition, anti-microbial activity and insecticidal activity. They are found in a variety of tropical plants from the Rubiaceae and Violaceae families.
 |
| The structure of kalata B1 showing the distorted beta-sheet topology and the loop nomenclature enabled by the cyclic backbone. |
Cyclotides are small disulfide rich peptides isolated from plants.Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the Rubiaceae, Violaceae, and Cucurbitaceae families. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae.,
Cyclotides have been reported to have a wide range of biological activities, including anti-HIV, insecticidal, anti-tumour, antifouling, anti-microbial, hemolytic, neurotensinantagonism, trypsin inhibition, and uterotonic activities. An ability to induceuterine contractions was what prompted the initial discovery of kalata B1.
The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.
The cyclotides have been recognised as a family of novel circular proteins only in the last few years but the discovery of the first member of this family may be traced back to reports of native medicine applications in the early 1970s.
Kalata B1, was discovered because it is an active ingredient in a herbal medicine used by African women to assist childbirth . While on a Red Cross relief effort in the Congo region in the 1960s a Norwegian doctor, Lorents Gran, noted that during labour African women often ingested a tea made from leaves of the plant Oldenlandia affinis because of its uterotonic effects. The active ingredient was determined to be a peptide that was named kalata B1, after the local name for the native medicine. Subsequent in vivo studies in rats confirmed uterotonic activity of the purified peptide but it was not characterised as a macrocyclic peptide until some 20 year later.
The mid-1990�s was a key period in the discovery of macrocyclic peptides, with several independent groups discovering such peptides while screening for various biological activities and our group determining the three dimensional structure of kalata B1 . In the first fortuitous discovery Sch�pke et al., examined Viola arvensis and V. tricolor in a study aimed at the discovery of new saponins. While assaying for the usual hemolytic activity of saponins they discovered a macrocyclic peptide, violapeptide I, with hemolytic activity. At around the same time bio-assay driven screens for anti-HIV and anti-neurotensin activity led to the discovery of the circulins and cyclopsychotride A respectively.
 |
| Viola arvensis a cyclotide containing plant. Member of the violaceae family and found in temperate regions of Australia and Europe. |
With our report of the three dimensional structure of kalata B1 in 1995 and its sequence homology with the circulins and cyclopsychotride A, we became convinced that macrocyclic peptides might be more common than had earlier been thought and we began searching for other examples. Several other macrocyclic peptides were found in the late 1990s and it became clear that the peptides formed part of a family that we subsequently named the cyclotides.
Several novel cyclotide sequences have been discovered in the last few years , with the known sequences now exceeding 45 and many more currently being characterized in our laboratories. A large proportion of the new cyclotides have been discovered based on their structural properties rather than biological activities. The cyclotides are relatively hydrophobic and can be readily identified from crude plant extracts by their characteristically late elution on RP-HPLC.
The cyclotides described above, all come from plants in the Rubiaceae or Violaceae families but the prevalence of macrocyclic peptides has recently been expanded to include the Cucurbitaceae family. This is based on the discovery of the trypsin inhibitors MCoTI-I and MCoTI-II, 34 residue macrocyclic peptides, from Momordica cochinchinensis . They have no sequence homology to the previously characterized cyclotides, with the exception of the six cysteine residues, but are of a similar size and contain a cystine knot motif (Felizmenio-Quimio, 2001). The MCoTI peptides were originally isolated based on their trypsin inhibitory activity and are homologous to linear cystine knot peptides from the squash family of trypsin inhibitors such as EETI-II and CMTI.
References
Bokesch HR, Pannell LK, Cochran PK, Sowder RC, 2nd, McKee TC and Boyd MR: A novel anti-HIV macrocyclic peptide from Palicourea condensata. J. Nat. Prod. (2001) 64:249-250.
Broussalis AM, Goransson U, Coussio JD, Ferraro G, Martino V and Claeson P: First cyclotide from Hybanthus (Violaceae). Phytochemistry (2001) 58:47-51.
Claeson P, G�ransson U, Johansson S, Luijendijk T and Bohlin L: Fractionation protocol for the isolation of polypeptides from plant biomass. J. Nat. Prod. (1998) 61:77-81.
Craik DJ, Daly NL, Bond T and Waine C: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J. Mol. Biol. (1999) 294:1327-1336.
G�ransson U, Luijendijk T, Johansson S, Bohlin L and Claeson P: Seven novel macrocyclic polypeptides from Viola arvensis. J. Nat. Prod. (1999) 62:283-286.
Gran L: Isolation of oxytocic peptides from Oldenlandia affinis by solvent extraction of tetraphenylborate complexes and chromatography on sephadex LH-20. Lloydia (1973a) 36:207-208.
Gran L: On the effect of a polypeptide isolated from “Kalata-Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol. Toxicol. (1973b) 33:400-408.
Gustafson KR, Sowder II RC, Henderson LE, Parsons IC, Kashman Y, Cardellina II JH, McMahon JB, Buckheit Jr. RW, Pannell LK and Boyd MR: Circulins A and B: Novel HIV-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia. J. Am. Chem. Soc. (1994) 116:9337-9338.
Hallock YF, Sowder RCI, Pannell LK, Hughes CB, Johnson DG, Gulakowski R, Cardellina JHI and Boyd MR: Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J. Org. Chem.(2000) 65:124-128.
Hernandez JF, Gagnon J, Chiche L, Nguyen TM, Andrieu JP, Heitz A, Trinh Hong T, Pham TT and Le Nguyen D: Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure. Biochemistry (2000) 39:5722-5730.
Saether O, Craik DJ, Campbell ID, Sletten K, Juul J and Norman DG: Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry (1995) 34:4147-4158.
Sch�pke T, Hasan Agha MI, Kraft R, Otto A and Hiller K: H�molytisch aktive komponenten aus Viola tricolor L. und Viola arvensis Murray. Sci. Pharm. (1993) 61:145-153.
Witherup KM, Bogusky MJ, Anderson PS, Ramjit H, Ransom RW, Wood T and Sardana M: Cyclopsychotride A, A biologically active, 31-residue cyclic peptide isolated from Psychotria Longipes. J. Nat. Prod. (1994) 57:1619-1625.
Extracting the Medicine from Traditional Chinese Medicine-Used as sedative and a painkiller in Oriental medicine
Nardostachys chinensis.
Extracting the Medicine from Traditional Chinese Medicine
Nardostachys chinensis or “Gansong” – a medicinal plant in the family Valerianaceae – is used as a sedative and a painkiller in Oriental medicine. Jun Zhou, Chinese Academy of Sciences, Kunming, and colleagues have isolated a new type of sesquieterpenoid–chalcone hybrid, containing a 2,3-dihydrofuran ring fused to an aristolane-type sesquiterpenoid and a chalcone, nardokanshone A (pictured).
- Zhang, X; Lan Z, Dong XP, Deng Y, Hu XM, Peng T, Guo P. (January 2007). “Study on the active components of Nardostachys chinensis”. Zhong Yao Cai: 38–41. PMID 17539300. Retrieved 12 June 2013.
Merck and Lupin collaborate to co-market Merck’s Pneumovax 23 Pneumococcal polysacharide vaccine for Indian market
%200.5%20mL407.GIF)
Pneumococcal polysaccharide vaccine (PPSV) — the latest version is known asPneumovax 23 (PPV-23) — is the first pneumococcal vaccine, the first vaccine derived from a capsular polysaccharide, and an important landmark in medical history. The polysaccharide antigens were used to induce type-specific antibodies that enhanced opsonization, phagocytosis, and killing of pneumococci by phagocytic cells. The pneumococcal polysaccharide vaccine is widely used in high-risk adults. As a result, there have been important reductions in the incidence, morbidity, and mortality from pneumococcal pneumoniae and invasive pneumococcal disease.
First used in 1945, the tetravalent vaccine was not widely distributed, since its deployment coincided with the discovery of penicillin. In the 1970s, Robert Austrian championed the manufacture and distribution of a 14-valent PPSV. This evolved in 1983 to a 23-valent formulation (PPSV23). A significant breakthrough impacting the burden of pneumococcal disease was the licensing of a protein conjugate heptavalent vaccine (PCV7) beginning in February 2000.
Ayurveda- Obesity control
Currently, Indian anti-obesity drug market is bifurcated into prescription and non-prescription. Amongst the prescription anti-obesity drug market there is only one drug – Orlistat that is been used globally. While the other anti-obesity drugs, Rimonabant and Sibutramine were banned by Indian government in 2009 and 2010 as side-effects were found in those drugs.
According to the experts, the market size of anti-obesity for prescription drug (generic Orlistat) is Rs 40 crore. While market size of non-prescription drug mostly herbal and ayurvedic drugs is estimated at Rs 500 crore in India. The global anti-obesity drug market is expected to reach $11 billion by 2017.
Orlistat is originally made by multinational drug company Roche that markets the prescription drug under the brand/trade name Xenical. The drug’s patent protection ended in 2009. Currently, there is plethora of generic drug makers like Ranbaxy, Intas Pharma, Biocon Ltd, Torrent Pharma, Troikaa Pharma and Mankind Pharmaceuticals that makes generic copies of Orlistat in India.
http://ijrap.net/admin/php/uploads/870_pdf.pdf
http://nopr.niscair.res.in/bitstream/123456789/6269/1/IJTK%208(4)%20602-605.pdf
anti obesity drugs
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as overweight (pre-obese) when their BMI is between 25 kg/m2 and 30 kg/m2, and obese when it is greater than 30 kg/m
Obesity increases the likelihood of various diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis. Obesity is most commonly caused by a combination of excessive dietary calories, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to support the view that some obese people eat little yet gain weight due to a slow metabolism is limited; on average obese people have a greater energy expenditure than their thin counterparts due to the energy required to maintain an increased body mass.
The primary treatment for obesity is dieting and physical exercise. To supplement this, or in case of failure, anti-obesity drugs may be taken to reduce appetite or inhibit fat absorption. In severe cases, surgery is performed or an intragastric balloon is placed to reduce stomach volume and/or bowel length, leading to earlier satiation and reduced ability to absorb nutrients from food.
Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century. Obesity is stigmatized in the modern Western world, though it has been perceived as a symbol of wealth and fertility at other times in history, and still is in many parts of Africa.[
Excessive body weight is associated with various diseases, particularly cardiovascular diseases, diabetes mellitus type 2, obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been found to reduce life expectancy.
Obesity is one of the leading preventable causes of death worldwide. Large-scale American and European studies have found that mortality risk is lowest at a BMI of 22.5–25 kg/m in non-smokers and at 24–27 kg/m2 in current smokers, with risk increasing along with changes in either direction. A BMI above 32 has been associated with a doubled mortality rate among women over a 16-year period. In the United States obesity is estimated to cause an excess 111,909 to 365,000 death per year, while 1 million (7.7%) of deaths in the European Union are attributed to excess weight On average, obesity reduces life expectancy by six to seven years: a BMI of 30–35 reduces life expectancy by two to four years, while severe obesity (BMI > 40) reduces life expectancy by 10 year
Causes
At an individual level, a combination of excessive caloric intake and a lack of physical activity is thought to explain most cases of obesity. A limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. In contrast, increasing rates of obesity at a societal level are felt to be due to an easily accessible and palatable diet,[64] increased reliance on cars, and mechanized manufacturing. A 2006 review identified ten other possible contributors to the recent increase of obesity: (1) insufficient sleep, (2) endocrine disruptors (environmental pollutants that interfere with lipid metabolism), (3) decreased variability in ambient temperature, (4) decreased rates of smoking, because smoking suppresses appetite, (5) increased use of medications that can cause weight gain (e.g., atypical antipsychotic), (6) proportional increases in ethnic and age groups that tend to be heavier, (7) pregnancy at a later age (which may cause susceptibility to obesity in children), (8) epigenetic risk factors passed on gene rationally, (9) natural selection for higher BMI, and (10) assortative mating leading to increased concentration of obesity risk factors (this would not necessarily increase the number of obese people, but would increase the average population weight).[67] While there is substantial evidence supporting the influence of these mechanisms on the increased prevalence of obesity, the evidence is still inconclusive, and the authors state that these are probably less influential than the ones discussed in the previous paragraph.
Ways of preventing Obesity
Dieting
Main article: Dieting
Diets to promote weight loss are generally divided into four categories: low-fat, low-carbohydrate, low-calorie, and very low calorie. A meta-analysis of six randomized controlled trials found no difference between three of the main diet types (low calorie, low carbohydrate, and low fat), with a 2–4 kilogram (4.4–8.8 lb) weight loss in all studies. At two years these three methods resulted in similar weight loss irrespective of the macronutrients emphasized.[132]
Very low calorie diets provide 200–800 kcal/day, maintaining protein intake but limiting calories from both fat and carbohydrates. They subject the body to starvation and produce an average weekly weight loss of 1.5–2.5 kilograms (3.3–5.5 lb). These diets are not recommended for general use as they are associated with adverse side effects such as loss of lean muscle mass, increased risks of gout, and electrolyte imbalances. People attempting these diets must be monitored closely by a physician to prevent complications.
Exercise
With use, muscles consume energy derived from both fat and glycogen. Due to the large size of leg muscles, walking, running, and cycling are the most effective means of exercise to reduce body fat. Exercise affects macronutrient balance. During moderate exercise, equivalent to a brisk walk, there is a shift to greater use of fat as a fuel. To maintain health the American Heart Association recommends a minimum of 30 minutes of moderate exercise at least 5 days a week.
A meta-analysis of 43 randomized controlled trials by the Cochrane Collaboration found that exercising alone led to limited weight loss. In combination with diet, however, it resulted in a 1 kilogram weight loss over dieting alone. A 1.5 kilogram (3.3 lb) loss was observed with a greater degree of exercise. Even though exercise as carried out in the general population has only modest effects, a dose response curve is found, and very intense exercise can lead to substantial weight loss. During 20 weeks of basic military training with no dietary restriction, obese military recruits lost 12.5 kg (27.6 lb). High levels of physical activity seem to be necessary to maintain weight loss. A pedometer appears useful for motivation. Over an average of 18-weeks of use physical activity increased by 27% resulting in a 0.38 decreased in BMI.
Signs that encourage the use of stairs as well as community campaigns have been shown to be effective in increasing exercise in a population. The city of Bogota, Colombia for example blocks off 113 kilometers (70 miles) of roads every Sunday and on holidays to make it easier for its citizens to get exercise. These pedestrian zones are part of an effort to combat chronic diseases, including obesity.
Weight loss programs
Weight loss programs often promote lifestyle changes and diet modification. This may involve eating smaller meals, cutting down on certain types of food, and making a conscious effort to exercise more. These programs also enable people to connect with a group of others who are attempting to lose weight, in the hopes that participants will form mutually motivating and encouraging relationships.
A number of popular programs exist, including Weight Watchers, Overeaters Anonymous, and Jenny Craig. These appear to provide modest weight loss (2.9 kg, 6.4 lb) over dieting on one’s own (0.2 kg, 0.4 lb) over a two year period. Internet-based programs appear to be ineffective. The Chinese government has introduced a number of “fat farms” where obese children go for reinforced exercise, and has passed a law which requires students to exercise or play sports for an hour a day at school (see Obesity in China).
Medication
Main article: Anti-obesity medication
The two most commonly used medications to treat obesity: orlistat (Xenical) and sibutramine (Meridia)
Only two anti-obesity medications are currently approved by the FDA for long term use.[147] One is orlistat (Xenical), which reduces intestinal fat absorption by inhibiting pancreatic lipase; the other is sibutramine (Meridia), which acts in the brain to inhibit deactivation of the neurotransmitters norepinephrine, serotonin, and dopamine (very similar to some anti-depressants), therefore decreasing appetite. Rimonabant (Acomplia), a third drug, works via a specific blockade of the endocannabinoid system. It has been developed from the knowledge that cannabis smokers often experience hunger, which is often referred to as “the munchies”. It had been approved in Europe for the treatment of obesity but has not received approval in the United States or Canada due to safety concerns.[148][149] European Medicines Agency in October 2008 recommended the suspension of the sale of rimonabant as the risk seem to be greater than the benefits.
Weight loss with these drugs is modest. Over the longer term, average weight loss on orlistat is 2.9 kg (6.4 lb), sibutramine is 4.2 kg (9.3 lb) and rimonabant is 4.7 kg (10.4 lb). Orlistat and rimonabant lead to a reduced incidence of diabetes, and all three drugs have some effect on cholesterol. However, there is little information on how these drugs affect the longer-term complications or outcomes of obesity. In 2010 the FDA noted concerns that sibutramine increases the risk of heart attacks and strokes in patients with a history of cardiovascular disease.
There are a number of less commonly used medications. Some are only approved for short term use, others are used off-label, and still others are used illegally. Most are appetite suppressants that act on one or more neurotransmitters. Phendimetrazine (Bontril), diethylpropion (Tenuate), and phentermine (Adipex-P) are approved by the FDA for short term use, while bupropion (Wellbutrin), topiramate (Topamax), and zonisamide (Zonegran) are sometimes used off-label.
The usefulness of certain drugs depends upon the comorbities present. Metformin (Glucophage) is preferred in overweight diabetics, as it may lead to mild weight loss in comparison to sulfonylureas or insulin. The thiazolidinediones, on the other hand, may cause weight gain, but decrease central obesity.[155] Diabetics also achieve modest weight loss with fluoxetine (Prozac), orlistat and sibutramine over 12–57 weeks. Preliminary evidence has however found higher number of cardiovascular events in people taking sibutramine verses control (11.4% vs. 10.0%). The long-term health benefits of these treatments remain unclear.
Fenfluramine and dexfenfluramine were withdrawn from the market in 1997, while ephedrine (found in the traditional Chinese herbal medicine má huáng made from the Ephedra sinica) was removed from the market in 2004. Dexamphetamines are not approved by the FDA for the treatment of obesity due to concerns regarding addiction.[147] the use of these drugs is not recommended due to potential side effects. However, people do occasionally use these drugs illegally.
Surgery
Main article: Bariatric surgery
Bariatric surgery (“weight loss surgery”) is the use of surgical intervention in the treatment of obesity. As every operation may have complications, surgery is only recommended for severely obese people (BMI > 40) who have failed to lose weight following dietary modification and pharmacological treatment. Weight loss surgery relies on various principles: the two most common approaches are reducing the volume of the stomach (e.g. by adjustable gastric banding and vertical banded gastroplasty), which produces an earlier sense of satiation, and reducing the length of bowel that comes into contact with food (gastric bypass surgery), which directly reduces absorption. Band surgery is reversible, while bowel shortening operations are not. Some procedures can be performed laparoscopically. Complications from weight loss surgery are frequent.
Surgery for severe obesity is associated with long-term weight loss and decreased overall mortality. One study found a weight loss of between 14% and 25% (depending on the type of procedure performed) at 10 years, and a 29% reduction in all cause mortality when compared to standard weight loss measures. A marked decrease in the risk of diabetes mellitus, cardiovascular disease and cancer has also been found after bariatric surgery. Marked weight loss occurs during the first few months after surgery, and the loss is sustained in the long term. In one study there was an unexplained increase in deaths from accidents and suicide, but this did not outweigh the benefit in terms of disease prevention. When the two main techniques are compared, gastric bypass procedures are found to lead to 30% more weight loss than banding procedures one year after surgery.
The effects of liposuction on obesity are less well determined. Some small studies show benefits while others show none. A treatment involving the placement of an intragastric balloon via gastroscopy has shown promise. One type of balloon lead to a weight loss of 5.7 BMI units over 6 months or 14.7 kg (32.4 lb). Regaining lost weight is common after removal, however, and 4.2% of people were intolerant of the device.
Other Home Remedies
Honey: Mix one teaspoon of honey with two teaspoons of lime juice and some pepper. Drink this at least once a day.
Boiled Water: Drink a glass of boiled water every day after a meal.
Ginger Tea: Drink ginger tea 2-3 times a day.
Black Pepper: Seasoning foods with black pepper will decrease the need for salts and fats, and will still add flavor to foods. This will also help reduce weight.
Cinnamon: This spice can act as a low calorie sweetener to help reduce the amount of sugar needed in a recipe. It also adds a unique flavor to most cookie recipes.
Shudh Guggulu: Take Guggulu with a teaspoon of ginger and honey twice a day. This helps increase a body’s metabolism.
Trifla: This is another diet aid that contains amalaki, bibbitaki, and haritaki. This should be taken at least once a day if one chooses to use this supplement.
Raw or Cooked Cabbage: The intake of cabbage reduces the conversion of sugars to fat. Therefore, eating plenty of this well help increase the body’s ability to metabolize fatty foods.
Vitamin B-12: Take a vitamin B-12 tablet at least once daily. For further information on vitamin usage, read the directions on the vitamin bottle, and consult a doctor for more information. This vitamin comes also in leafy dark green vegetables, so eat many of these as often as possible.
Ayurvedic Medicines for Obesity
- Traphala Capsules
- Shuddha Guggulu Capsules
- Morslim-Z slimming Capsules of Obesity
When one follow the above diet recommendations and partake in one or more of the ayurvedic remedies, that person will be cured from obesity.
When not sure about how to apply herbal remedies or diet tablets, one should consult an ayurvedic specialist who is trained to help people in determining correct dosage. This is especially true for children inflicted with any disease, but is true for everyone. All medicines should be taken within the recommended guidelines.
Commiphora mukul ,Guggul
- as a binding agent only from modern perspective. Ayurveda mentions its use as anti-inflammatory, anti-obesity, uterine tonic, anti-hypercholesterolemic and immodulatory
- dose of the gum resin is from 5 to 50 grain used in placenta previa,amenorrhoea,dysmenorrhoea sore nipples,gonorrhea and ringworm
- how it is purified for gynecological disorders and what is the anupana
- purification of gum guggul (loban in unani medicine) – resin is soaked in water and left for some time . the supernatant water is decanted off. this process may be repeated once again. the vessel containing the dissolved resin is placed in the open and dried, that is the water is allowed to evaporate. drying may effected mechanically also.the resin to be employed will be in the form of an extract.
- Guggulu is considered to be a binding agent, though they have not used this term.
Acharya Sharangadhara mentions in Madhyama khanda 7/3….
Kuryad Avahnisiddena kwachid Gugguluna vatim!!
To prepare tablets without application of heat, Guggulu is added and tablets are advised to prepare. Here Guggulu acts as a binding agent only. - Lipid-lowering effects: Guggul (gum guggul) is a resin produced by the mukul mirth tree. Guggulipid is extracted from guggul using ethyl acetate. The preparation produced by extraction with petroleum ether is called a fraction A. Typical guggulipid preparations contain 2.5-5% of the plant sterols guggulsterones E and Z. These two components have been reported to exert effects on lipids.Several hypotheses have been advanced to explain these effects on lipids. Guggulsterones, particularly guggulsterone -pregnadiene-3,16-dione), have been reported to function as antagonists of the farsenoid X receptor (FXR) and the bile acid receptor (BAR), nuclear hormones which are involved with cholesterol metabolism and bile acid regulation. It has been reported that guggulsterone does not exert its lipid effects on mice lacking FXR. Other publications have proposed that guggul may inhibit lipogenic enzymes and HMG-Co A reductase in the liver. increase uptake of cholesterol by the liver via stimulation of LDL receptor binding. directly activate the thyroid gland and/or increase biliary and fecal excretion of cholesterol.
- Antioxidant effects: Guggul extracts have been reported to possess antioxidant properties possibly mediating protection against myocardial necrosis
- Platelet effects: Guggulipid has been found to inhibit platelet aggregation and increase fibrinolysis
- Anti-inflammatory: the results of several studies suggest possible anti-inflammatory and antiarthritic activities of guggul. On a per-microgram basis, guggulipid appears to be significantly less potent than indomethacin or hydrocortisone. Possible effects on high-sensitivity C-reactive protein (hs-CRP) have recently been observed in a clinical trial.
- Guggul has been a key component in ancient Indian Ayurvedic system of medicine. But has become so scarce because of its overuse in its two habitats in India where it is found — Gujarat and Rajasthan that the World Conservation Union (IUCN) has enlisted it in its Red Data List of endangered species.Guggul produces a resinous sap known as gum guggul. The extract of this gum, called gugulipid, guggulipid or guglipid, has been used in Ayurvedic medicine, a traditional Hindu medicine, for nearly 3,000 years in India. The active ingredient in the extract is the steroid guggulsterone, which acts as an antagonist of the farnesoid X receptor, once believed to result in decreased cholesterol synthesis in the liver. However, several studies have been published that indicate no overall reduction in total cholesterol occurs using various dosages of guggulsterone, and levels of low-density lipoprotein (“bad cholesterol”) increased in many people.
- Guggul is sought for its gummy resin, which is harvested from the plant’s bark through the process of tapping. In India and Pakistan, guggul is cultivated commercially. The resin of the guggul plant, known as gum guggulu, has a fragrance similar to that of myrrh and is commonly used in incense and perfumes. It is the same product that was known in Hebrew, ancient Greek and Latin sources as bdellium.Guggul can be purchased in a loosely packed form called dhoop, an incense from India, which is burned over hot coals. This produces a fragrant, dense smoke. The burning coals which let out the smoke are then carried around to different rooms and held in all corners for a few seconds. This is said to drive away evil spirits as well as remove the evil eye from the home and its family members.
Enbrel (etanercept), Biosimilar innovator drug companies scrambling to copy
Enbrel (etanercept)
http://www.biosimilarnews.com/enbrel-patent-in-the-us
Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product.
Amgen announced the issuance of U.S. Patent No. 8,063,182 related to Enbrel (etanercept).owned by Hoffmann-la roche and licensed to Amgen (exp2028) VIA immunex
A biosimilar etanercept, manufactured in China by CP Guojian Pharmaceutical Co., Ltd. (Shanghai), is already being marketed in China as Yisaipu [3] and in Colombia as Etanar [4]. Several biotechnology companies in Asia are also developing biosimilar versions of tumor necrosis factor inhibitors. Protalix Biotherapeutics, Inc. (Carmiel, Israel) is developing a biosimilar etanercept that is expressed in plant cells [5]. Mycenax Biotech (Taiwan) has completed early-phase clinical trials of a biosimilar etanercept in Southeast Asia: a phase I trial among 24 healthy subjects in South Korea and a phase I/II trial that enrolled 18 patients with rheumatoid arthritis in Taiwan [6]. Avesthagen (Bangalore, India) has received a patent from the Indian patent office for a biosimilar etanercept [7]. In South Korea, both Celltrion (Yeonsu-gu Incheon City) and Aprogen (Daejeon) are developing a biosimilar of infliximab [8] and LG Life Sciences (Seoul) is developing biosimilars of both etanercept and infliximab to treat rheumatoid arthritis and other inflammatory diseases [9].
Drug developers:
- Avesthagen: Avent™ in clinical studies
read this doc
http://www.avesthagen.com/docs/020910pr.pdf
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- BioXpress Therapeutics: Biosimilar in active development
http://www.bioxpress.com/pipeline/
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- Cipla:Etacept, Launches biosimilar in India on April 17, at a price of Rs. 6,150 ($113.43), 30% less than the innovator product.
- read this
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- Hanwha Chemical: HD203 “scheduled for launch,” company states on its website without including a date, following submission for marketing approval to South Korea’s Korea Ministry of Food and Drug Safety following completion of Phase I and Phase III trials. Hanwha has said it will seek a partner to commercialize HD203 and a biosimilar for Herceptin (trastuzumab).
- http://www.thepharmaletter.com/file/105028/merck-co-links-with-koreas-hanwha-on-biosimilar-of-enbrel.html
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- LG Life Sciences: LBEC0101 completed Phase I trial in South Korea
http://www.lgls.co.kr/rd/pipeline.jsp
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- Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea
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- Protalix Biotherapeutics: PRX-106 in preclinical studies
http://www.protalix.com/product-development/prx-106.asp
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- Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China
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Recently discontinued effort: Merck & Co. and Hanwha Chemical: Hanwha disclosed December 18, 2012, that Merck terminated agreement to develop and manufacture the biosimilar MK-8953, now called HD203, as well as market it in all countries except South Korea and Turkey, an up to $720 million deal signed June 2011.1
Nature and indication: Tumor necrosis factor (TNF) blocker for rheumatoid arthritis, polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged two years or older; psoriatic arthritis; ankylosing spondylitis; and plaque psoriasis
2012 sales: $7.963 billion (includes $4.236 billion Amgen + $3.737 billion Pfizer). Amgen markets Enbrel in U.S. and Canada under an agreement with Pfizer set to expire October 31, 2013
Patent status: Patents set to expire in EU in 2015; in U.S., 2019, 2023, 2028, and 2029
Etanercept is a fusion protein produced by recombinant DNA, which fuses a soluble human TNF receptor with an IgG1 antibody. This modified protein works by blocking TNF activity, thereby reducing their ability to cause an inflammatory response as well as severe, chronic pain and discomfort to patients. The fusion protein is protected by five different molecule Key patent families (Fig 2) and are all considered to be a constraint to generic entry until expiry. Although the patent families are owned by different patentees, Amgen have entered into licensing agreements with all parties allowing them sole distributing and marketing rights of Enbrel®.
- Public Health Service Act Sec. 262. Regulation of biological products.http://www.fda.gov/RegulatoryInformation/Legislation/ucm149278.htm
- Woodcock J, Griffin J, Behrman R, Cherney B, Crescenzi T, Fraser B, Hixon D, Joneckis C, Kozlowski S, Rosenberg A, Schrager L, Shacter E, Temple R, Webber K, Winkle H. The FDA’s assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6:437–442. doi: 10.1038/nrd2307. [PubMed] [Cross Ref]
- Yisaipu. http://www.cpgj-pharm.com/en/product_patient.asp?proid=22&action=intro
- Rondon F, Bautista A, Salazar JC, Casas N, Santos P, Vargas F, Marquez J. Etanar therapy in real-life patients with rheumatoid arthritis [abstract]Arthritis Rheum. 2010;62(Suppl 10):1811.
- Pipeline products. http://www.protalix.com/pipeline_products.html
- Biosimilar TuNEX® completes Phase I/II clinical trial in Taiwan, Phase I in Korea. http://www.mycenax.com.tw/webe/html/02news/news_show.aspx?page=1
- Singh K. Avesthagen gets patent for Enbrel biosimilar. Economic Times. 2010.
- Korea’s Celltrion and Aprogen in race to sell biosimilars in Japan.http://sis.windhover.com/buy/abstract.php?id=28101102003
- LG Life Sciences’ Pipeline Overview. http://thinklgls.com/rnd/pipeline
- Dr. Reddy’s Marketed Pharmaceutical Products.http://www.drreddys.com/products/bio_mproducts.html#
- TL011 in severe, active rheumatoid arthritis patients.http://clinicaltrials.gov/ct2/show/NCT01123070
- GP2013 in the treatment of RA patients refractory to or intolerant of standard therapy. http://www.clinicaltrials.gov/ct2/show/NCT01274182
- View Opportunities. http://www.sourcegenerics.com/viewAllListing.asp
- Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FE, Cookfair DL, Simon JH, Jacobs LD. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)Neurology. 1998;50:1266–1272. [PubMed]
- Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–475. doi: 10.1056/NEJMoa011931. [PubMed] [Cross Ref]
- Schellekens H, Jiskoot W. Eprex-associated pure red cell aplasia and leachates. Nat Biotechnol. 2006;24:613–614. doi: 10.1038/nbt0606-613.[PubMed] [Cross Ref]
- Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408. doi: 10.1056/NEJMoa040528. [PubMed] [Cross Ref]
- Federal Food, Drug, and Cosmetic Act (FD&C Act) SEC. 505. [21 USC §355] New Drugs.http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm108125.htm
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: European Medicines Agency; 2005.
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: European Medicines Agency; 2006.
- European Medicines Agency. Work plan for the biosimilar medicinal products working party (BMWP) 2011. London: European Medicines Agency; 2010.
- H. R. 3590–686. Patient Protection and Affordable Care Act. Title VII– Improving Access to Innovative Medical Therapies. Subtitle A–Biologics Price Competition and Innovation. Sec. 7002. Approval Pathway for Biosimilar Biological Products.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf
- Implementation of the Biologics Price Competition and Innovation Act of 2009.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
see details of etanercept
Etanercept
ATC (Anatomical Therapeutic Chemical Classification)
L04AA11,L04AB01
CAS registry number (Chemical Abstracts Service)
0185243-69-0
Chemical Formula
C2224-H3472-N618-O701-S36
Molecular Weight
51238
Therapeutic Categories
Immunosuppressant
Disease-modifying antirheumatic drug, DMARD
Biological response modifier, BRM
Anti-inflammatory agent
Tumor necrosis factor alpha (TNF-α) inhibitor
Chemical Name
Dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1
is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein.
• Sandoz continues to advance biosimilar pipeline with seven Phase III trials across five molecules
• Global program underscores Sandoz’s leadership in biosimilarsHolzkirchen, Germany, June 24, 2013 – Sandoz, the global leader in biosimilars, announced it has initiated a major Phase III clinical trial with its biosimilar version of etanercept (Amgen’s Enbrel®).
Read more at
http://www.drugs.com/news/novartis-begins-enbrel-phase-iii-trial-45414.html
| Etanercept (trade name Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid andpsoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the “master regulator” of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha. Etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody. First, the developers isolated the DNA sequence that codes the human gene for soluble TNF receptor 2, which is a receptor that binds to tumor necrosis factor-alpha. Second, they isolated the DNA sequence that codes the human gene for the Fc end of immunoglobulin G1 (IgG1). Third, they linked the DNA for TNF receptor 2 to the DNA for IgG1 Fc. Finally, they expressed the linked DNA to produce a protein that links the protein for TNF receptor 2 to the protein for IgG1 Fc.The prototypic fusion protein was first synthesized and shown to be highly active and unusually stable as a modality for blockade of TNF in vivo in the early 1990s by Bruce A. Beutler, an academic researcher then at the University of Texas Southwestern Medical Center at Dallas, and his colleagues.[2][3][4] These investigators also patented the protein, selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.It is a large molecule, with a molecular weight of 150 kDa., that binds to TNFα and decreases its role in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα.In North America, etanercept is co-marketed by Amgen and Pfizer under the trade name Enbrel in two separate formulations, one in powder form, the other as a pre-mixed liquid. Wyeth is the sole marketer of Enbrel outside North America excluding Japan whereTakeda Pharmaceuticals markets the drug.Etanercept is an example of a protein-based drug created using the tools of biotechnologyand conceived through an understanding afforded by modern cell biology.  |
Figure 2: Molecule Key Patents landscape
International Market
Patents protecting the various technologies of the Etanercept molecule (Fig. 2) across all five families have now expired in Europe, Canada and Australia. In Europe, SPCs and paediatric extensions were granted based on the EP0418014 (1989-09-05) and EP0939121 (1989-09-12) however the last of the paediatric extensions expired in early August, 2015. Finland has been granted a national patent disclosing the Etanercept sequence in the family with priority US40324189A (1989-09-05), which would constrain generic entry until April, 2020. Cyprus has also received a five year patent extension on a national patent set to expire in mid-2016 and would be a constraint for biosimilars entering the market there.
Although the Etanercept molecule is no longer protected in the European, Canadian or Australian markets, no biosimilar has been approved in these major markets suggesting the difficulty of developing a biosimilar which complies with the stringent regulatory pathways in place. Having said that, Merck and Samsung Bioepis (a joint venture from electronics giant Samsung and biotech firm Biogen Idec) has submitted their Etanercept biosimilar candidate SB4 to the EMA, which is currently awaiting review. If approved, it is expected that they will obtain further approval in other territories where Etanercept is no longer protected. With the regulatory approval pathways differing from country to country, Etanercept biosimilars have been approved in smaller markets including India, China and South Korea.
US Market
In the US, the ‘molecule’ patents protecting active ingredient Etanercept have all expired aside from US8,063,182 (‘182) and US8,163,522 (‘522) members from priority CH331989 (1989-09-12) owned by Roche (exclusively licensed to Amgen), which are set to expire in 2028 and 2029, respectively. These patents members disclose a portion of the Etanercept sequence, so are considered to constrain biosimilar entry until expiry. The members are continuation patents filed from US5,610,279 (another member of the same family) and while they were both filed in May, 1995, were not issued until 2011 (‘182) and 2012 (‘522). Under the 35 U.S. Code § 154, these patents received 17 year patent term from the issuing date. Since these patents were applied for in 1995 during the transitional period of the TRIPS agreement, they were not published by the USPTO until they were issued. This situation often gives rise to the term ‘submarine patents’.
Currently there is no system to link relevant patents to biologic drugs in the US as with small molecule drugs (Orange Book) which makes filing biosimilars in the US a convoluted process. While the FDA are currently working on an equivalent to the Orange Book, the ‘Purple book’, companies wishing to develop biosimilars in the US need to do considerable patent landscape searching in order to avoid infringement of any patents potentially protecting the biologic drug. In the case of US member ‘182 and ‘522, upon inspection these patents are clearly relevant to Enbrel®, however without a registry there is no easy way of making this link. The patents have been flagged in the Key Patent module in Ark due to SPCs and paediatric extensions on the equivalent EP0939121 member and litigation in the US (see below).
Currently, biologic drugs approved in the US receive a 12 year data exclusivity period and in Europe, an 8 year data exclusivity period with additional 2 year market exclusivity, starting from the market authorisation date. Enbrel® was approved in 1998 and 2000, in the US and Europe, respectively and data exclusivity protection has therefore now expired.
Development of biosimilars takes considerably longer than generic medicine making it a costly venture for generic pharmaceutical manufacturers. According to Amgen, Enbrel® was protected by US5395760 (‘760) and US5605690 (‘690) members from priority 1989-09-05 which were set to lose patent protection in 2012 and 2014, respectively. In 2004, Sandoz began developing GP2015 a biosimilar equivalent of Etanercept, investing millions of dollars in the hope that they would be ready to launch by the time all the patent protection for Enbrel® expired. Currently, GP2015 is in Phase III study in the US and European Union for patients with moderate to severe chronic plaque-type psoriasis with respect to PASI 75 response rate at Week 12.
In June 2013, Sandoz filed a suit against Amgen and Roche in the US District Court for the Northern District of California seeking declaratory judgment of non-infringement, invalidity and unenforceability of the ‘182 and ‘522 patents. Sandoz claimed a ‘case of controversy’ regarding the patents, as their research and development was based on the understanding that ‘760 and ‘690 patents members were protecting Enbrel®. With the issuing of ‘182 and ‘522 patents this has essentially delayed the prospect of an Etanercept biosimilar from entering the US market until 2029.
Amgen and Roche sought a dismissal of the proceeding due to lack of subject matter jurisdiction, which was granted. Although Sandoz appealed the decision, the Court of Appeals affirmed the dismissal, since there was no real and immediate controversy as Sandoz had not yet filed an FDA application, and they had based their suit on future events and were not able to establish “real and immediate injury or threat of future injury.”
Generic Licensing News-SPIRAMYCIN Featured product
SPIRAMYCIN
Spiramycin is a macrolide antibiotic. It is used to treat certain types of infections that are caused by bacteria. It is most commonly used to treat infections of the lung, skin, and mouth.
Spiramycin is sometimes used to treat gonorrhea for people who are allergic to penicillin. Spiramycin is also used as an alternative agent in the treatment of toxoplasmosis during pregnancy.
Spiramycin is a macrolide antibiotic. It is used to treat toxoplasmosisand various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2]
Spiramycin has been used in Europe since the year 2000 under thetrade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacibasi Ilae, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.
Spiramycin is a 16-membered ring macrolide (antibiotic). It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium sp., Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration
- Spiramycin advanced consumer information | Drugs.com
- Toxoplasmosis at MayoClinic.com
Actavis to Launch Generic Epilepsy/Bipolar Drug
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| LAMOTRIGINE |
PARSIPPANY, N.J., July 15, 2013 (AP) — Drugmaker Actavis Inc. said Monday it’s received U.S. approval to sell a generic version of Lamictal, a tablet for treating epilepsy and bipolar disorder.
Actavis, based in Parsippany, N.J., said the Food and Drug Administration has granted approval for it to sell lamotrigine tablets in doses of 25, 50, 100 and 200 milligrams.http://www.pharmalive.com/actavis-to-launch-generic-epilepsybipolar-drug
Lamotrigine, marketed in the US and most of Europe as Lamictal /ləˈmɪktəl/ byGlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used off-label as an adjunct in treating depression. For epilepsy, it is used to treat focal seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Like many other anticonvulsant medications, Lamotrigine also seems to act as an effective mood stabilizer, and has been the first U.S.Food and Drug Administration (FDA)-approved drug for this purpose since lithium, a drug approved almost 30 years earlier. It is approved for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants (due to lamotrigine’s being aphenyltriazine), lamotrigine has many possible side-effects. Lamotrigine is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs,but it could have additional actions since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and carbamazepine and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel blocking antiepileptic drugs are not. In addition, lamotrigine shares few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties. Lamotrigine is inactivated by hepatic glucuronidation.
Soliris Gets Thumbs Up From EMA’s COMP
eculizumab
CAS number 219685-50-4
Alexion’s Soliris® (eculizumab) Receives Positive Opinion from the Committee for Orphan Medicinal Products for Treatment of Neuromyelitis Optica (NMO)
Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN) today announced that Soliris® (eculizumab), the company’s first-in-class terminal complement inhibitor, has received a positive opinion for orphan medicinal product designation from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) for the treatment of neuromyelitis optica (NMO), a life-threatening, ultra-rare neurological disorder. The positive opinion of the COMP has now been forwarded to the European Commission for final approval and publication in the community register. Soliris is not approved in any country for the treatment of patients with NMO
http://www.pharmalive.com/soliris-gets-thumbs-up-from-emas-comp
Soliris is a formulation of eculizumab which is a recombinant humanized monoclonal IgG2/4;κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.
Eculizumab (INN and USAN; trade name Soliris®) is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare, progressive, and sometimes life-threatening disease characterized by excessive destruction of red blood cells (hemolysis).[1] It costs £400,000 ($US 600,000) per year per patient.[1]
Eculizumab also is the first agent approved for the treatment of atypical hemolytic uremic syndrome (aHUS), an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body, leading to kidney failure, damage to other vital organs and premature death.[2][3]
In clinical trials in patients with PNH, eculizumab was associated with reductions in chronic hemolysis, thromboembolic events, and transfusion requirements, as well as improvements in PNH symptoms, quality of life, and survival.[1][4][5][6] Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA),[7] the formation of blood clots in small blood vessels throughout the body,[1][3][4] including normalization of platelets and lactate dehydrogenase (LDH), as well as maintenance or improvement in renal function.[7]
Eculizumab was discovered and developed by Alexion Pharmaceuticals and is manufactured by Alexion. It was approved by the United States Food and Drug Administration (FDA) on March 16, 2007 for the treatment of PNH, and on September 23, 2011 for the treatment of aHUS. It was approved by the European Medicines Agency for the treatment of PNH on June 20, 2007, and on November 24, 2011 for the treatment of aHUS. Eculizumab is currently being investigated as a potential treatment for other severe, ultra-rare disorders
- Hillmen, Young, Schubert, P, N, J, et al (2006). “The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria”.N Engl J Med 355 (12): 1233–1243. doi:10.1056/NEJMMoa061648. PMID 16990386.
- Noris, Caprioli, Bresin, M, J, E, et al. (2010). “Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype”. Clin J Am Soc Nephrol 5: 1844–1859.
- Caprioli, Noris, Brioschi, J, M, S, et al (2006). “Genetics of HUS: the impact of MPC, CFH, and IF mutations on clinical presentation, response to treatment, and outcome”. Blood 108: 1267–1279.
- Hillman, Hall, Marsh, P, C, JC, et al (2004). “Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria”. N Eng J Med 350: 552–559.
- Ray, Burrows, Ginsberg, Burrows, JG, RF, JS, EA (2000). “Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient”. Haemostasis 30: 103–107.
- Kelly, Hill, Arnold, RJ, A, LM, et al (2011). “Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival”. Blood 117: 6786–6792.
- .Soliris® (eculizumab) prescribing information (2011). Cheshire, CT: Alexion Pharmaceuticals.http://www.soliris.net/sites/default/files/assets/soliris)pi.pdf.
Novartis investigational drug LDK378, a selective inhibitor of (ALK), shows a marked clinical response ….49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013
LDK378
J. Med. Chem. 2013, DOI:10.1021/jm400402q).
- CAS Number:
- 1032900-25-6
- Mol. Formula:
- C28H36ClN5O3S
- MW:
- 558.13
Novartis investigational drug LDK378, a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013.
Doctors and patients are clamoring for more ways to fight lung cancer, the leading cause of cancer deaths in the U.S., of which NSCLC is the most common form. In March, LDK378 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA). The designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies.
Currently, two Phase II clinical trials are actively recruiting patients worldwide. One study focuses on patients with ALK+ NSCLC who were previously treated with chemotherapy and crizotinib (NCT01685060). The second study examines LDK378 in patients who are crizotinib-naive (NCT01685138). In addition, Phase III clinical trials are planned to begin in the coming months, aiming to enroll more than 1,100 patients with ALK+ NSCLC at sites worldwide. Novartis plans to file for approval the drug in early 2014.
Chemical Name of LDK378
5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
Chemical Synthesis of LDK378
Technical Data of LDK378
1H NMR (400 MHz, DMSO-d6 + trace D2O) δ 8.32 (s,1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56 – 4.48(m, 1H), 3.49 – 3.32 (m, 3H), 3.10 - 2.91 (m, 3H), 2.09 (s, 3H), 1.89 – 1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H+).
The compound LDK378, a highly selective inhibitor of ALK, has been granted “Breakthrough Therapy Designation” by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).
ClinicalTrials.gov. A Dose Finding Study With Oral LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK) (Phase 1). http://www.http://clinicaltrials.gov/show/NCT01283516; Accessed June 7, 2013; currently recruiting participants.
ClinicalTrials.gov. LDK378 in crizotinib naïve adult patients with ALK-activated non-small cell lung cancer (Phase 2). http://www.clinicaltrials.gov/ct2/show/NCT01685138; Accessed June 7, 2013; currently recruiting participants.
ClinicalTrials.gov. LDK378 in adult patients with ALK-activated NSCLC previously treated with chemotherapy and crizotinib (phase 2) http://www.clinicaltrials.gov/ct2/show/NCT01685060; Accessed June 7,2013; currently recruiting participants.
Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007).
Alice Tsang Shaw, et al., Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC; 2013 ASCO Annual Meeting; Abstract Number: 8010; Citation: J Clin Oncol 31, 2013 (suppl; abstr 8010)
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