Archive for the ‘Education’ Category
Sanford-Burnham robots speed up path to discovery
Last Updated on Saturday, 24 July 2010 04:26 Written by admin Thursday, 8 July 2010 10:40
The work force at Lake Nona’s Sanford- Burnham Institute includes 90 scientific staffers, 60 administrators and support personnel — and a team of three robots. The robots are part of a $15 million investment from the National Institutes of Health and occupy a large, glass-enclosed room on the bottom floor of Burnham’s Lake Nona campus.
Although they resemble the robotic arms used in automobile assembly lines, these robots have a far different task: filling test tubes faster than a human being. And that, scientists say, will speed up the process of scientific discovery.
“The robots are from the automobile industry,” said Greg Roth, director of medicinal chemistry at Burnham’s Conrad Prebys Center for Chemical Genomics. “We use them because of the accuracy and precision of their movements.”
The robotic arms can fill miniature test-tube “wells” so tiny that 1,536 of them fit on a plate the size of an index card. Using such small test tubes allows researchers to save money on chemicals and compounds.
After filling the wells, the robotic arms take a plate of the tubes and subject them to numerous tests such as varying temperatures and pressures. The robots are connected to a main computer that compiles the data from the millions of tests.
Pharmaceutical companies developed the ultra-high throughput screening technology in the mid-1990s, but universities and nonprofit research institutions such as Burnham did not have access to the robots until recently.
Funded by NIH, the Burnham center and eight others around the country form the institute’s Molecular Libraries Production Centers Network. This resource library and network assists scientists in research and allows results to be shared across the public and private sectors.
The reason for the federal government’s interest? As the results of the Human Genome Project began pouring in, scientists found themselves with so many avenues to explore that they needed faster research procedures.
“My scientists like to say they can do more than a robot, but they can only do it for a day,” said Michelle Palmer, director of screening for the Broad Institute at Harvard and Massachusetts Institute of Technology.
“The humans can do it faster and better, but they can’t sustain it. We need to sustain this over months of effort and get it done exactly the same way every time,” Palmer said.
Formulation strategies for improving drug solubility using solid dispersions
Last Updated on Wednesday, 5 May 2010 10:23 Written by Editor Wednesday, 5 May 2010 10:23
Abstract:
The solubility behavior of drugs remains one of the most challenging aspects in formulation development. Solid dispersions have been employed to enhance the dissolution rates of poorly water – soluble drugs. This article reports various solubility enhancement strategies in solid dispersion. The approaches described are fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology. The paper also highlights the potential applications and limitations of these approaches in solid dispersions.
Keywords: micronization, lyophilization, melt agglomeration, extruding, amorphous state, bioavailability, solubility, dissolution
Introduction:
Drug substances are seldom administered alone, but rather as part of a formulation in combination with one or more non-medicinal agents that serve varied and specialized pharmaceutical function. The proper design and formulation of a dosage form requires consideration of the physical, chemical and biological characteristics of all the drug substances and pharmaceutical ingredients to be used in fabricating the product. An important physical-chemical property of a drug substance is solubility, especially aqueous system solubility. Solubility is a predetermined and rate limiting step for absorption. Drugs must have to enter in to the systemic circulation to exert a therapeutic effect1. In recent technologies, innovation of combinatorial chemistry and high throughput screening can effectively discover the seeds of new drugs which exhibit good pharmacological activities however 35-40 % of these new drugs discovered by those technologies suffer from poor aqueous solubility2-3. Consideration of the modifed Noyes-Whitney equation 4, 5 provide some hints regarding how the dissolution rate of very poorly soluble compounds improved to minimize the limitations to oral bioavailability:
dC /dt = AD(Cs – C) / h
where dC/dt is the rate of dissolution, A is the surface are available for dissolution, D is the diffusion coefficient of the compound, Cs is the solubility of the compound in the dissolution medium, C is the concentration of drug in the medium at time t and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound. To increase the dissolution rate from equation the following approaches are available.
a) To increases the surface area available for dissolution by:
b)Decreasing the particle size of drug.
c)Optimizing the wetting characteristics of compound surface.
d)To decrease the boundary layer thickness
e)Ensure sink condition for dissolution
f)Improve apparent solubility of drug under physiologically relevant conditions. Drug administered in fed state is a way to improve the dissolution rate6. The solubility/dissolution behavior of a drug is key determinant to its oral bioavailability, the latest frequency being the rate-limiting step to absorption of drugs from the gastrointestinal tract7-8. Consequently poor solubility results in low bioavailability, increase in the dosage, large inters and intra-subject variation and large variations in blood drug concentrations under fed versus fasted conditions. Improvement of oral bioavailability of poor water-soluble drugs remains one of the most challenging aspects of drug development. The techniques/ approaches that have commonly been used to overcome drawbacks associated with poorly water-soluble drugs, in general includes micronization, salt formation, use of surfactant and use of pro- drug 7-8 however all these techniques have certain limitations.  Micronization has several disadvantages, the main one being the limited opportunity to control important characters of the final particle such as size, shape, morphology, surface properties and electrostatic charges. In addition micronization is a high-energy process, which causes disruptions in the drug s crystal lattice, resulting in the presence of disordered or amorphous regions in the final product. The amorphous regions are thermodynamically unstable and are therefore susceptible to recrystallization upon storage, particularly in hot and humid conditions9, 10, 11 . All poorly water-soluble drugs are not suitable for improving their solubility by salt formation. The dissolution rate of a particular salt is usually different form that of parent compound. However sodium and potassium salts of weak acids dissolve more rapidly than the free salts. Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide and water resulting in precipitation of poorly water-soluble drug, epigastric distress due to high alkalinity. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as patient compliance and commercialization. Even though particle size reduction increases the dissolution rate, the formed fine powders showing poor wettability and flow properties. Solid dispersion technique has come into existence to eliminate all these problems 12-13. Solid dispersion (SD) technique has been widely used to improve the dissolution rate, solubility and oral absorption of poorly water-soluble drugs14-15. In solid dispersion the drugs are dispersed in a biologically inert matrix for the intention of enhancing oral bioavailability. Chiou and Riegelman defined these systems as the dispersion of one or more active ingredient in an inert carrier matrix at solid state prepared by the melting (fusion), solvent or melting-solvent method.16 However, the most attractive option for increasing the release rate is improvement of the solubility through formulation approaches.
Table 1 summarizes the various approaches that can be taken to improve the solubility or to increase the available surface area for dissolution. Review articles have already been published on the use of polymorphs 17, the amorphous form of the drug 18 and complexation 19, 20.
Solubility enhancement strategies in solid dispersions:
Various strategies investigated by several investigators include fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology.
Fusion method:
The fusion process is technically the less difficult method of preparing dispersions provided the drug and carrier are miscible in the molten state. This process employs melting of the mixture of the drug and carrier in metallic vessel heated in an oil bath, immediately after fusion, the sample are poured onto a metallic plate which is kept at ice bath. A modification of the process involves
Spray congealing from a modified spray drier onto cold metal surface. Decomposition should be avoided and is affected by fusion time and rate of cooling21-22. Another modification of the above method, wherein SD(s) of troglitazone- polyvinyl pyrrolidone (PVP) k 30 have been prepared by closed melting point method. This method involves controlled mixing of water content to physical mixtures of troglitazone PVP k30 by storing at various equilibrium relative humidity levels (adsorption method) or by adding water directly (charging method) and then mixer is heated. This method is reported to produce SD with 0% apparent crystallinity23. On the other hand, the fusion process does not require an organic solvent but since the melting of sparingly water-soluble drug and water-soluble polymer entails a cooling step and solid pulverizing step, a time consuming multiple stage operation is required. To overcome this problem Nakano et al 24 have described a method conceptualizing the formation of a SD as the solid-to-solid interaction between a sparingly water soluble drug, nilvadipine and water soluble polymer which, unlike conventional production method, comprises mixing a sparingly water soluble drug and water soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, instead of heating the system to the extent that the two materials are melted , the sparingly water soluble drug can be made amorphous to have never been achieved by any dry process heretofore known.
Solvent evaporation method:
The solvent-based process uses organic solvent to dissolve and intimately disperse the drug and carrier molecule. Large volumes of solvents are generally required which can give rise to toxicological problems 25-26. Many investigators studied SD of meloxicam, naproxen27-28, rofecoxib29, felodipine30, atenolol 31, and nimesulide32 using solvent evaporation technique. These findings suggest that the above-mentioned technique can be employed successfully for improvement and stability of solid dispersions of poor water drugs. Suhagic et al. 33 prepared SD of etoricoxib using PEG and PVP as a carriers by solvent evaporation method where carriers along with drug were dissolved in 2-propanol to get a clear solution followed by solvent evaporation and finally dispersion was collected. The prepared SD(s) exhibited improved dissolution attributed to decreased crystallinity, improved wetting and improved bioavailability.
Lyophillization technique:
Freeze-drying involves transfer of heat and mass to and from the product under preparation34. Lyophillization has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. Betageri et al. 35, Topalogh et al. 36, Badry et al. 37 and Fathy et al.38 have successfully investigated the potential applications of lyophilization in manufacturing of SD(s). Drooge et al39 suggested spray freeze-drying as a potential alternative to the above-mentioned process to produces 9- tetrahydrocannabino containing inulinbased solid dispersions with improved incorporation of – tetrahydrocannabino in inulin.
Melt agglomeration process:
This technique has been used to prepare SD where the binder acts as a carrier. Binder (carrier), drug and excipients are heated to temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high shear mixer40. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates41. Larger particles results in densification of agglomerates while fine particle cause complete adhesion to the mass to bowl shortly after melting attributed to distribution and coalescence of the fine particles41-43.
Extruding method:
The extruding method was originally designed as an extraction / casting method for polymer alloys in plastic industry, is now used to process cereals and functionalize food materials, such as tissue products from animal proteins44. Hot melt extrusion approach represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt extruder where only thermo stable components are relevant45. The extruder consists of a hooper, barrel, a die, a kneading screw and heaters. The physical mixture is introduced into the hopper that is forwarded by feed screw and finally is extruded from the die44. The effect of screw revolution speed and water content on the preparation of SD(s) should be investigated, since these parameters have profound impact on the quality of SD(s). Nakamichi et al 46, studied that presence of kneading paddle element of screw results in super saturation on dissolution testing while slow revolution rate of screw and addition of the suitable amount of water increased rate of dissolution although no super saturation occurred. In addition, high screw speed high feed rate processes in comparison with low screw speed low feed rate processes caused an increase in extrudate radius and porosity and decrease in mechanical strength and drug release rate from the matrix attributed to the expansion promoted under certain extrusion conditions47. To reduce the melt viscosity in the extrudate and to be able to decrease temperature settings, a plasticizer can be added to the formulation. Typically, conventional plasticizer such as triacetin or polyethylene glycol is used in concentration range of 5-30 % weight of the extrudate that lowers the processing temperature. Carbon dioxide can act as temporary plasticizer. During extrusion carbon dioxide is transformed in gaseous phase. As a consequence carbon dioxide escapes from extrudate and does not appear in final product48. The role of methylparaben49 and sorbitol50 has also been investigated as plasticizer in preparation of SD(s) in extrusion method. This method has already been used successfully to prepare SD(s) of i traconazole and hydroxypropylmethylecellulose (HPMC) 51, indomethacin/lacidipine/nefidipine/ piroxicam/ tobutamide and polyvinylpyrrolidone (PVP) 52, itraconazole53 and HPMC 2910/ Eudragit e 100 or a mixture of Eudragit E 100-PVP vinyl acetate 64 to improve solubility and dissolution rate of poor water soluble drugs.
Spray drying:
The manufacture of milk powder was one of the first applications of spray drying when the method was developed in 1920. Today, spray drying finds great utility in pharmaceutical industry because of the rapid drying and specific characteristics such as particle size and shape of the final product. In addition, it is simple and cost effective, as it is 30-50 times less expensive than freeze-drying. It is an established method that is initiated by atomizing suspensions or solutions into fine droplets followed by a drying process, resulting solid particles. The process allows production of fine, dust free powder as well as agglomerated one to precise specifications. The operating conditions and dryer design depends upon the drying characteristics of the product and require powder specifications 54-56. Rankell et al. prepared SD(s) of loperamide with PEG 6000 by this technique wherein solutions containing different concentrations of PEG 6000 and constant amount of loperamide were spray dried. After spray drying, the dispersions were dried at 400C under vacuum until constant weight. Solvent used was dichloromethane. The prepared SD(s) exhibited higher dissolution rates than that of pure crystalline loperamide57. Chouhan et al 58 studied the suitability of this technique for preparation of SD(s) of glibenclamide polyglcolized glycerides. This study revealed the improvement in solubility and dissolution rates, also improvement in the therapeutics efficacy of amorphous glibenclamide in SD(s) was observed. Some other investigators 59-60 also reported improvement in solubility and dissolution rate. The frequent use of the organic solvent in spray drying pose problems such as residues in products, environmental pollution and operational safety as well as corporate problems such as capital investment. Tanno et al61described a process for producing the SD(s) of poorly water-soluble drugs using water-soluble polymer dispersion and/ or water-soluble polymer solution and the plasticizer solution by using 4-nozzle spray gun. The spray drying technique is a useful method to obtain spherical particle and narrow distribution. The role of porous materials such as calcium silicate, controlled pore glass and porous cellulose is appreciated to formulate solid dosages forms because they confer special characteristics such as decrease of melting point and a decrease in the crystallinity of drug entrapped in pores. In addition, porous materials control polymorphs and stabilizes meta-stable crystals in SD(s) under sever storage conditions. Moreover, porous silica has been reported to improve solubility and dissolution rates of indomethacin and tolbutamide 62-63.
The use of surfactant:
The utility of the surfactant systems in solubilization is well known. Surfactant reduces hydrophobicity of drug by reducing interfacial or surface tension because of these unique property surfactants have attracted the attention of investigators for preparation of solid dispersions64- 65. Recently a new class of surfactant known as Gelucires are introduced which identify by melting points and HLB values. Gelucire is a widely use in the formulation of semi solid dispersions. Gelucire is a saturated polyglycolized glyceride consisting of mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol (PEG) derived from natural vegetable fatty acids and having amphiphilic character. Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and higher HLB ones for fast release. Gelucire 44/14 and gelucire 50/13 are two examples of this synthetic group where 44 and 50 represent melting point, while 14 and 313 represent HLB values of gelucire respectively 66-67. Solid dispersions of antiviral agent uc-781-polyethylene glycol 6000- gelucire 44/14 and UC-781- PEG 6000-gelucire 44/14- PVP k 30 were studied. Improvement in solubility, dissolution and stability was observed 68-69. Labrasol, of same chemical nature as gelucire, is a clear liquid surfactant with a HLB of 14. Solid dispersions of piroxicam with labrasol have also resulted in improved solubility and dissolution when compared with pure drug 66-67. The amphiphilic poly (ethylene oxide)-poly (propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) block polymers, known as poloxamer or pluronics represent another class of surfactants. These are available in various molecular weights and PEO/PPO ratios, and hence offer a large variety of physico-chemical properties 70. These block polymers are extensively used in the pharmaceutical industry as defoaming agents, gelling agents, detergents, dispersing agents, emulsifying agents and solubilizing agents71. When used in relatively high quantities, poloxamer imparts sustained-release properties to solid dosage forms, by forming a lipid matrix72. Solid dispersions using pluronic F-68 (a type of poloxamer) as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water- soluble compound. Results showed that the solid dispersion substantially increased the in vitro-dissolution rate of ABT-963. A significant increase of oral bioavailability compared with conventional capsule formulation was also reported73. The presence of water and polar water-miscible solvent, a partially water-miscible solvent, a non- ionic surfactant, an anionic surfactant and cationic surfactant affect domain of the PEO-PPO-PEO block copolymer selfassembly74. Therefore, organic solvents and surfactants should be used with great care for preparation solid dispersion while using in combination with poloxamer. Inutec SPI, a derivative of inulin prepared by the reaction between isocyanates and the polyfructose backbone in the presence of a basic catalyst such as a tertiary amine or lewis acid, has also been evaluated as carrier in formulation of solid dispersions for a poorly water- soluble drug. Inutec SPI has low viscosity and stability effect on emulsion and suspension. Dissolution properties of SD(s) made up of itraconazole and Inutec SPI were improved in comparison to pure itraconazole or physical mixtures with Inutec SPI4. Hemant et al 75 and Sheen et al 76 studied that polysorbate 80, a commonly used surfactant, results in improvement of dissolution and bioavailability of poorly watersoluble drug attributed to solubilization effect of surface active agent. Polysorbate 80 also ensues complete release of drug in metastable finely dispersed state having large surface area.
Super critical fluid (scf) technology:
This technology has been introduced in the late 1980s and early 1990s, and experimental proofs of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds, polymers and biopolymers, explosives and energy materials, superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. Since the first experiences of Hannay et al in 1879, a number of techniques have been developed and patented in the field of SCF-assisted particle design. These methods use. SCFs either as solvent: rapid expansion from supercritical solution (RESS) or anti-solvent: gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gas-saturated solution (PGSS). Conventional methods, i.e. Spray drying, solvent evaporation and hot melt method often result in low yield, high residual solvent content or thermal degradation of the active substance79. Solution enhanced dispersion by supercritical fluids (SEDS), aerosol solvent extraction system (ASES), supercritical anti-solvent (SAS), gas anti-solvent (GAS) and precipitation with a compressed fluid anti-solvent (PCA) are process of micronization. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing cocurrently80. The use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature81. Supercritical fluids used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component) 82. Wong et al compared the SD(s) of felodipine prepared by conventional solvent evaporation (CSE) and supercritical antisolvent precipitation (SAS) methods. The particle sizes of the SD(s) from CSE process increased at 1h after dispersed in distilled water. However the particle sizes of the SD(s) from SAS process were maintained for 6 h due to the increased solubility of felodipine. Moreover, SD(s) form the SAS process showed a high dissolution rate of over 90% within 2 h showing the potential applications of SCE technology in preparation of SD(s) 83.
Summary And Future Potential:
The solubility of drugs in aqueous media is a key factor highly influencing their dissolution rate and bioavailability following oral administration resulting in low bioavailability. Solubility enhancement of these drugs remains one of the most challenging aspects of drug development. A variety of devices have been developed over the years to enhance the drug solubility and dissolution of the drugs. The solid dispersion method is one of the effective approaches to achieve the goal of solubility enhancement of poorly water-soluble drugs. Various techniques, described in this review, are successfully used for the preparation of SD(s) in the bench and lab scale and can be used at industrial scale also. Solid dispersions came into limelight in pharmaceutical development due to the increasing number of drug candidates which are poorly soluble and the substantial improvements in the manufacturing methods for solid dispersions that have been made in the last few years. Although there are some hurdles like scale up and manufacturing cost to overcome, there lies a great promise that solid dispersion technology will hasten the drug release profile of poorly water soluble drugs.
Acknowledgements:
I am very much thankful to my research guide and co- guide, Dr.N.M.Patel and Dr.M.M.Patel respectively for their constant encouragement and help to write this review.
References:
1. Ansel H C, Allen L V and Popovich CG. Eds. In; Pharmaceutical dosage forms and drug delivery systems, 7th Edn, Lippincott Williams and Wilkins, 2000, 60-61,66.
2. Ohara T, Kitamura S, Kitagawa T and Terada K. Dissolution mechanism of poorly water- soluble drug from extended solid dispersion system with ethyl cellulose and hydroxypropyl
methylcellulose. Int. J. Pharm. 302, 2005, 95-102.
3. Mooter G V den, Weuts I, Rider T D and Blaton N. Evaluation of Inutec SPI as a new carrier in the formulation of solid dispersion for poorly water drugs. Int. J.Pharm. 316, 2006, 1-6.
4. A.A. Noyes, W.R. Whitney, The rate of solution of solid substances in their own solutions, J. Am. Chem. Soc. 19 (1897) 930-934.
5. W. Nernst, Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen, Zeitschrift f.  Physik. Chemie 47 (1904) 52-55.
6. E. Galia, E. Nicolaides, D. HoÈrter, R. LoÈbenberg, C. Reppas, J.B. Dressman, Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs, Pharm.  Res. 15 (1998) 698-705.
7.Patro S, Himasankar K, Choudhury A A and Rao M E B. Effect of some hydrophilicpolymers on dissolution rate of roxitromycin. Indian J. Pharm. Sci. 67(3), 2005, 334-341.
8.Omaima A S, Mohammed A H, Nagia A M and Ahmed S Z. Formulation and optimization of mouth dissolve tablets containing rofecoxib solid dispersions. AAPSÂ PharmSciTech 7(2), 2006, E1-E9.
9.Hecq J, Deleers M, Fanara D, Vranckx H and Amighi K. Preparation and characterization of nanaocrystals for solubility and dissolution rate enhancement of nifidipine. Int. J. Pharm. 299,  2005,167-177.
10.Takano, Niichiro, Kawashima, Hiroyuki, Shinoda, Yasuo, Inagi and Toshio. Solid dispersion compositions. United States Patent No. 6753330, 2004.
11.Yiyun C, Tongwen X and Rongqiang F. Polyamidoamine dendrimers used as solubility
enhances of ketoprofen. Eur. J. Med. Chem. 40, 2005, 1390-1393.
12.Mohan Babu G V M, Prasad D S, and Raman Murthy K V. Evaluation of modified gum karaya as carrier for the dissolution enhancement of poorly water-soluble drug Nimodipine. Int. J. Pharm. 234, 2002, 1-17.
13.Gibaldi M. Ed., In; Biopharmaceutics and clinical pharmacokinetics, 4th Edn, Pharma Book Syndicate, Hyderabad, 2005, 48
14.Tanaka N, Imai K, Okimoto K, Ueda S, Rinta Ibuki Y T, Higaki K and Kimura T. Development of novel sustained-release system, disinmtegration-controlled matrix tablet (DCMT) with solid dispersion granules of nilcadipine (II): In vivo evaluation. Journal of controlled release 122, 2006, 51- 56.
15.Duncan Q M C. The mechanism of drug release from solid dispersions in water-soluble polymers. Int. J. Pharm. 231, 2002, 131-144.
16.Hayes, Davis, Morella and Angelo Mario. Pharmaceutical compositions for poorly water-soluble drugs. United States Patent. No. 6881745,2005.
17.J.-O. Henck, U.J. Griesser, A. Burger, Polymorphie von Arzneistoffen, Pharm. Ind. 59 (1997) 165-169.
18.B.C. Hancock, G. Zografi, Characteristics and significance of the amorphous state in pharmaceutical systems (review), J. Pharm. Sci. 86 (1997) 1-12.
19. D. Hoerter, J.B. Dressman, Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract (review), Adv. Drug Delivery Rev. 25 (1997) 3-14.
20. T.Loftsson, M.E. Brewster, Pharmaceutical application of cyclodextrins.Drug solubibilisation and stabilization (review), J.Pharm. Sci. 85 (1996) 1017-1025
21.Zerrouk N, Chemtob C, Arnaud P, Toscani S Â and Dugue J. In vitro and in vivo evaluation of carbemazepine-PEG 6000 solid dispersions. Int. J. Pharm. 225, 2001, 49-62.
22.Boral A, Sen N, Ghosh L K and Gupta B K. Solid Dispersion technology for controlling drug release and absorption. The eastern pharmacist, April 1995, 141-143.
23. Hasegawa S, Hamaura T, Furuyama N, Kusai A, Yonemochi E and Terada K. Effects of water contents in physical mixture and heating temperature on crystallinity of troglitazone- PVP K 30 solid dispersions prepared by closed melting method. Int. J. Pharm. 302, 2005, 103-112.
24. Nakano, Minoru, Uemura, Toshinobu, Morizane, Shinichi, Okuda, Kiyoshi, Nakata and Keiko. Method of producing a solid dispersion of a sparingly water-soluble drug, nilvadipine. United State Patent No. 5340591, 1994
25. Butler and Mattew J. Method of producing a solid dispersion of a poorly water-soluble drug. United State Patent No. 5985326,1999.
26. Kim Eun-Jung, Chun M K, Jang J S, Lee I H, K R L and Choi H K. Preparation of a solid  dispersion of felodipine using a solvent wetting method.
27.Chowdary K P R and R. Hymavathi. Enhancement of dissolution rate of meloxicam. Indian J. Pharm. Sci. April 2001, 150-154.
28. Rao M G, Suneetha R, Reddy P S and Ravi T K. Preparation and evaluation of solid dispersions of naproxen. Indian J. Pharm. Sci. 67(1), 2005,26-29.
29.Mura P, Zerrouk N, Mennini N, Masterly F and Chemtob C. Development and characterization of naproxen solid systems with improved drug dissolution properties. Eur. J. Pharm. Sci. 18, 2003, 67-75.
30.Soniwala M M, Patel P R, Mansuri N S, Parikh R K and Gohel M C. Indian J. Pharm. Sci 67(1), 2005, 61-65.
31.Moneghini M, Carcano A, Zingone G and Perissutti. Studies in dissolution enhancement of atenolol. Int. J. Pharm. 175, 1998, 177-183.
32.Jain R K, Sharma D K, Jain S, Kumar S and Dua J S . Studies on solid dispersions of  nimesulide with pregelatinized starch. Biosciences, biotechnology research Asia 3(1a), 2006, 151-153.
33.Suhagia B N, Patel H M, Shah S A, Rathod I and Parmar V K. Acta Pharm 56, 2006, 285-298.
34. Tsinontides S C, Rajniak P, Pham D, Hunke W  A, Placek, J and Reynolds S D. Freeze drying- principles and practice for successful scale-up to manufacturing. Int. J. Pharm. 280, No. 1, 2004,      1-16.
35. Betageri G V and Makarla K R. Enhancement of dissolution of Glyburide by solid dispersion and lyophilization techniques. Int. J. Pharm. 126, 1995, 155-160.
36.Yalcin T, Gulgun Y and Gonullu U. Inclusion of ketoprofen with skimmed milk by freeze-drying. Il Farmaco 54, 1999, 648-652.
37.Bandry M B and Fathy M. Enhancement of the dissolution and permeation rates of meloxicam by formation of its freeze-dried solid dispersions in polyvinylpyrrolidone K-30. Drug Dev. Ind. Pharm. 32 (2), 2006 Feb, 141-150.
38.Fathy M and Sheha M. In vitro and in vivo evaluation of an amylobarbitone /hydroxypropyl-betacyclodextrin complex prepared by a freeze-drying method. Pharmazie. 55 (7), 2000 Jul, 513-517.
39. Drooge D J V, Hinrichs W L J, Dickhoff H J, Elli M N A, Visser M R, Zijlastra G S and  Frijlink H W. Spray freeze drying to produce a stable 9- tetrahydrocannabino containing inulin based solid dispersion powder suitable for inhalation. Eur. J. Pharm. 26, 2005, 231-240.
40. Seo A, Holm P, Kristensen H G, Schaefer T. The preparation of agglomerates containing solid dispersions of diazepam by melts agglomeration in a high shear mixer. Int. J. Pharm. 259(1-2), 2003 Jun 18, 161-71.
41.Vilhelmsen T, Eliasen H, Schaefer T. Effect of a melt agglomeration process on agglomerates containing solid dispersions. Int. J. Pharm. 303(1- 2), 2005 Oct 13, 132-142.
42.Vilhelmsen T, Schaefer T. Agglomerate formation and growth mechanisms during melt agglomeration in a rotary processor. Int. J. Pharm. 304 (1- 2), 2005 Nov 4, 152-164.
43. Seo A and Schaefer T. Melt agglomeration with polyethylene glycol beads at a low impeller speed in a high shear mixer. Eur. J. Pharm. Biopharm. 52(3), 2001 Nov, 315-325.
44.Wang L, Cui F D, Hayse T and Sunada H. Preparation and evaluation of solid dispersion for nitrendipine- carbopol and nitrendipine HPMCP systems using twin screw extruder. Chem. Pharm. Bull. 53(10), 2005, 1240-1245
45.Zajc N, Obreza A, Bele M and Srcic S. Physical properties and dissolution behavior of   nefidipine/ mannitol solid dispersions prepared by hot melt method. Int. J. Pharm. 291, 2005, 51-58.
46.Nakamichi K, Nakano T, Yasuura H, Izumi S and Kawashima Y. The role of the kneading paddle and the effects of screw revolution speed and water content on the preparation of solid dispersions using a twin-screw extruder. Int. J. Pharm. 241(2), 2002 Jul 25, 203-211.
47. Six K, Verreck G, Peeters J, Brewster M and Van Den Mooter G. Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J. Pharm. Sci. 93(1), 2004 Jan, 124-131.
49.Verreck G, Decorte A, Heymans K, Adriaensen J, Liu D, Tomasko D, Arien A, Peeters J, Mooter G V den and Brewster M E. Hot stage extrusion of pamino salicylic acid with EC using CO2 as a temporary plasticizer. Int. J. Pharm. 327, 2006, 45 50.
50.Wu C and Mc Ginity J W. Influence of methylparaben as a solid-state plasticizer on the physicochemical properties of Eudragit RS PO hot-melt extrudates. Eur. J. Pharm. Biopharm. 56(1), 2003 Jul, 95-100.
51. Zajc N, Obreza A, Bele M and Srcic S. Physical properties and dissolution behavior of nefidipine/ mannitol solid dispersions prepared by hot melt method. Int. J. Pharm. 291, 2005,51-58.
52. Six K, Berghmans H, Leuner C, Dressman J, Van Werde K, Mullens J, Benoist L, Thimon M, Meublat L, Verreck G, Peeters J, Brewster M and Van den Mooter G. Characterization of solid dispersions of itraconazole and hydroxypropyl- methylcellulose prepared by melt extrusion, Part II. Pharm. Res. 20(7), 2003 Jul, 1047-1054.
53.Forster A, Hempenstall J, Tucker and Rades T. The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug Dev. Ind. Pharm. 27(6), 2001 Jul, 549-560.
54. Six K, Daems T, de Hoon J, Van Hecken A, Depre M, Bouche MP, Prinsen P, Verreck G, Peeters J, Brewster ME and Van den Mooter G. Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. Eur. J. Pharm. Sci. 24(2-3), 2005 Feb, 179-186.
55.Chronakisa I S, Triantafyllou A O, R O¨ ste. Solidstate characteristics and redispersible properties of powders formed by spray-drying and freeze-drying cereal dispersions of varying (1 3, 1 4)-ß -glucan content. Journal of cereal science 40, 2005, 183-193.
56.Patrice T T, Stephanie B and Hatem F. Preparation of redispersible dry nanocapsules by means of spray drying: Development and characterization. Eur. J. Pharm. Sci. 30, 2007, 124 135.
57. Rankell A S, Lieberman H A and Schiffmann R F. Drying. In: L. Lachman , H.A. Lieberman and J.L.Kanig eds. The theory and practice of industrial pharmacy. 3rd edition, Varghese Publishing house, Bombay, 1987, pp no 61.
58.Weuts I, Kempen D, Verreck G, Decorte A, Heymans K, Peeters J, Brewster M and Mooter G V den. Study of the physicochemical properties and stability of solid dispersions of loperamide and PEG 6000 prepared by spray drying. Eur. J. Pharm. Biopharm. 59, 2005, 119-126. Gelucire 44/14 and Labrasol . Il Farmaco 60,2005,777-782.
59. Chauhan B, Shimpi S and Paradkar A. Preparation and evaluation of glibenclamidepolyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. Eur. J. Pharm. Sci. 26,2005, 219-230.
60. Ueno Y, Yonemochi E, Tozuka Y, Yamamura S, Oguchi T and Yamamoto K. Characterization of amorphous ursodeoxycholic acid prepared by spray-drying. J. Pharm. Pharmacol. 50(11), 1998 Nov, 1213-1219
61.Chen R, Tagawa M, Hoshi N, Ogura T, Okamoto H and Danjo K. Improved dissolution of an insoluble drug using a 4-fluid nozzle spray-drying technique. Chem. Pharm. Bull. 52(9), 2004 Sep, 1066-1070.
62.Tanno, Fumie, Nishiyama and Yuichi. Process for producing a pharmaceutical solid preparation containing a poorly soluble drug. United states patent No. 6872336.
63.Takeuchi H, Nagira S, Yamamoto H and Kawashima Y. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. Int. J. Pharm. 293,2005, 155 164.
64.Takeuchi H, Nagira S, Yamamoto H and Kawashima Y. Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method. Powder technology141, 2004,187-195.
65.Ghebremeskel A N, Vemavarapu C and Lodaya M. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: Selection of polymer surfactant combinations using solubility parameters and testing the processability. Int. J. Pharm. 328, 2007, 119 -129.
66.Zhang R and Somasundaran P. Advances in adsorption of surfactants and their mixtures at solid/solution interfaces. Advances in colloid and interface science 123-126,2006,213-229.
67.Karatas A, Yüksel N and T Baykara. Improved solubility and dissolution rate of piroxicam usingGelucire 44/14 and Labrasol . Il Farmaco 60, 2005, 777-782.
68.Yükse N, Karatas A, Yalc¸ýn O¨ zkan, Ayhan Savas¸er, Sibel A. O¨ zkan and Baykara T. Enhanced bioavailability of piroxicam using Gelucire 44/14 and Labrasol: in vitro and in vivo evaluation. Eur. J. Pharm. Biopharm. 56, 2003, 453-459.
69.Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P and Mooter G Van den. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 10, 2000, 311 322.
70.Damian F, Blaton N, Kinget R and Mooter G Van den. Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K3. Int. J. Pharm. 244,2002, 87- 98.
71.Ivanova R, Lindman B and Alexandridis P. Effect of pharmaceutically acceptable glycols on the stability of the liquid crystalline gels formed by poloxamer 407 in water. J of Colloid and Interface Sci. 252, 2002,226 235.
72.Erlandsson B. Stability-indicating changes in poloxamers: the degradation of ethylene oxidepropylene oxide block copolymers at 25 and 40 Co. Polymer degradation and stabili ty 78,2002,571-575.
73.Jannin V, Pochard E and Chambin O. Influence of poloxamers on the dissolution performance and stability of controlled-release formulations containing Precirol® ATO 5. Int. J. Pharm. 309, 2006, 6- 15.
74.Chen Y, Zhang G G Z, Neilly J, Marsh K, Mawhinney D and Sanzgiri Y D. Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-6. Int. J. Pharm. 286, 2004, 69 80.
75.Ivanova R, Alexandridis P and Lindman B. Interaction of poloxamer block copolymers with  co solvents and surfactants. Colloids and Surfaces A: Physicochemical and Engineering Aspects 183 185,2001, 41 53.
76.Joshi H N, Tejwani R W, Davidovich M, Sahasrabudhe V P, Jemal M, Bathala M S, Varia S A and Serajuddin A T M. Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol Polysorbate 80 mixture. Int. J. Pharm. 269, 2004, 251 -258.
77.Sheen P C, Khetarpal V K, Cariola C.M and   Rowlings C E. Formulation studies of a poorly water-soluble drug in solid dispersions to improve bioavailability. Int. J. Pharm. 118, 1995, 221-227.
78.Hohman M M, Shin M, Rutledge G and Michael P. Brennera electrospinning and electrically forced jets. II. Applications. Physics of fluids, 13(8), 2001, 2221-2236.
79.Muhrer G, Meier U, Fusaro F, Albano S and Mazzotti M. Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: generation of drug microparticles and drug-polymer solid dispersions. Int. J. Pharm. 308,2006, 69-83.
80.Majerik V, Charbit G, Badens E, Horv´ath G, Szokonya L, Bosc N and Teillaud E. Bioavailability enhancement of an active substance by supercritical antisolvent precipitation. of Supercritical Fluids 40,2007, 101 110.
81.Taki S, Badens E and Charbit G. Controlled release system formed by supercritical anti-solvent coprecipitation of a herbicide and a biodegradable polymer. J of Supercritical Fluids 21,2001,61 70.
82.Manna L, Banchero M, Solta D, Ferri A, Ronchetii S and Sicrdi S. Impregnation of PVPÂ microparticles with ketoprofen in the presence of supercritical CO2. J of Supercritical Fluids 2006 article in press.
83.Dohrn R, Bertakis E, Behrend O, Voutsas E and Tassios D. Melting point depression by using supercritical CO2 for a novel melt dipersion micronization process. J of Molecular Liquids 131- 132, 2007, 53-59.
Table 1: Approaches to improve the solubility or to increase the available surface area for dissolution
| I. Physical modifications |
| Particle size |
| Micronization |
| Nanosuspensions |
| Modifications of the crystal habit |
| Polymorphs |
| Pseudopolymorphs (including solvates) |
| Complexation/solubilization |
| Use of surfactants |
| Use of cyclodextrines |
| Drug dispersion in carriers |
| Eutectic mixtures |
| Solid dispersions (non-molecular) |
| Solid solutions |
| II. Chemical modification |
| Soluble prodrugs |
| Salts |
Table 2:Methods for the characterization of solid dispersions
| Dissolution testing |
| Thermoanalytical methods: differential thermoanalysis and hot stage |
| Microscopy |
| Calorimetric analysis of the solution or melting enthalpy for calculation of |
| Entropy change |
| X-Ray diffraction |
| Spectroscopic methods, e.g. IR spectroscopy |
| Microscopic methods including polarization microscopy and scanning |
| Electron microscopy |
Table 3: Marketed formulation of solid dispersion
|
Drug Name |
Brand Name |
Company name |
|
Nelfinavir mesylate |
Viracept® |
Agouron Pharmaceuticals |
|
Ritonavir |
Norvir® |
Abbott Laboratories |
|
Amprenavir |
agenerase |
Glaxosmithkline |
|
Calcitriol |
Rocaltrol |
Roche |
|
Cyclosporine |
A/I neoral |
Novaritis |
|
Indomethacin |
Indomethacin |
Eisai Co |
About Authors:
Rajnikant C.Patel , Saiyad Masnoon, Madhabhai M. Patel, and Natvarlal M. Patel
Rajnikant C.Patel currently working as a lecturer and pursuing part time Ph.D. in the Department of Pharmaceutics at Kalol Institute of Pharmacy, Kalol- 38 27 21
Saiyad Masnoon studying in third year B.pharm at Kalol Institute of Pharmacy, Kalol- 38 27 21
Dr. Madhabhai M. Patel is a Principal in Kalol Institute of Pharmacy, Kalol- 38 27 21
Dr. Natvarlal M. Patel is a Principal in Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa
Source: pharmainfo.net
Posted under Drug Development, Education, Press Releases | No Comments
The difficulties of Cushing’s syndrome
Last Updated on Wednesday, 26 November 2008 01:55 Written by Editor Wednesday, 26 November 2008 01:55
Diagnosing and treating Cushing’s syndrome is sometimes just as difficult as it was 70 years ago.
For as long as it has been described, Cushing’s syndrome has presented physicians with a problem. Harvey Cushing first described it in 1932, and the diagnosis, differential diagnosis and treatment of Cushing’s have remained a major challenge for endocrinologists ever since.
Though uncommon, it is difficult to consider Cushing’s syndrome a rare occurrence. New research has shown Cushing’s syndrome to have a substantially higher prevalence than previously thought. Unexpected endogenous hypercortisolism may occur in 0.5% to 1% of patients with hypertension, 2% to 3% with poorly controlled diabetes, 6% to 9% with incidental adrenal masses and 11% with osteoporosis and vertebral fractures.
“We are gaining an appreciation that Cushing’s is more common than it was once believed to be,†said Mary Ruppe, MD, endocrinologist at the University of Texas Health Science Center at Houston, and program committee chair of the Women in Endocrinology organization. “This fact points to the need for data regarding the value of the different diagnostic approaches and for data regarding treatment/outcomes in populations with Cushing’s.â€
As most of the characteristics of Cushing’s are common in the general population, including obesity, depression and hypertension, it is extremely difficult for endocrinologists to decide on who should be screened for the disorder. A recent clinical review by Hershel Raff, PhD, and James W. Findling, MD, noted that as the number of patients in these high-risk groups continues to increase, the need for a sensitive and specific diagnostic test for Cushing’s syndrome has become paramount.
The three most commonly performed diagnostic studies for Cushing’s syndrome — urine-free cortisol, low-dose dexamethasone suppression test and the nocturnal salivary cortisol — are also not without hurdles. All three have been shown to produce false positives and false negatives.
Approximately 80% of patients with Cushing’s syndrome have an adrenocorticotropic-secreting neoplasm from a pituitary tumor (Cushing’s disease) or a nonpituitary neoplasm, and the treatment of Cushing’s disease remains challenging for both endocrinologists and neurosurgeons as well. Transsphenoidal surgery is currently the standard treatment of choice in patients, but achieving surgical remission has been difficult as well.
“Cushing’s syndrome is a very rare but important diagnosis for the patient and endocrinologist. Confirming the diagnosis may be challenging, and before embarking on a costly set of tests, the endocrinologist should be reasonably assured that the patient indeed requires diagnostic exclusion by rigorous screening methods,†said Shlomo Melmed, MD, senior vice president of Academic Affairs at Cedars Sinai Medical Center, Los Angeles, and an Endocrine Today editorial board member
.
With more than 7.5 decades of research since Dr. Cushing’s discovery, what are the best methods of diagnosis and treatment for Cushing’s syndrome? Endocrine Today talked with leading researchers in the field to uncover the current trends in Cushing’s syndrome treatment.
Screening process
Laurence Katznelson, MD, associate professor of medicine and neurosurgery at Stanford University, and medical director of the pituitary program at Stanford Hospital and Clinics, explained to Endocrine Today the difficulty of deciding who should be screened for Cushing’s syndrome. For instance, although the syndrome is associated with multiple comorbidities, including obesity, hypertension and depression, endocrinologists should be prepared to delve a little deeper into the symptoms to see if they warrant a screening test.
“The presence of Cushing’s syndrome should be considered if these medical conditions are present, though diagnostic testing should be performed only in subjects who have signs favoring Cushing’s, such as demonstration of objective proximal weakness, spontaneous ecchymoses and violaceous striae,†Katznelson said.
“For example, central obesity with supraclavicular and dorsicervical fat pads would favor a diagnosis of Cushing’s syndrome, in contrast to the presence of generalized obesity,†he said.
Raff and Findling noted in a recent clinical review that endogenous cortisol excess also leads to fairly specific catabolic effects — including the thinning of the skin with easy bruising, abdominal striae, poor wound healing, immune suppression, rib fractures, hirsutism in women, acne and muscle wasting leading to proximal muscle weakness.
“There is no clear guideline,†said Roberto Salvatori, MD, associate professor of medicine in the division of endocrinology at Johns Hopkins University School of Medicine. “You need to keep your mind open.â€
“Sometimes Cushing’s is obvious. Sometimes, when it is mild, it may not be diagnosed for many years. One must screen a lot of patients to find one with Cushing’s. However, anytime a physician thinks about the possibility of a patient having the disease, work-up should be initiated,†he said.
Testing options
Opinions varied when Endocrine Today asked researchers which of the three tests for Cushing’s syndrome was most reliable.
“No test is 100% sensitive or specific,†Salvatori said. “I always use two, sometimes three, screening tests.†However, Salvatori noted he feels the night-time salivary cortisol test is the most reliable and easy to obtain.
Raff and Findling described the measurement of free cortisol in a 24-hour urine collection as being long considered the gold standard for the diagnosis of endogenous hypercortisolism. The test relies on the concept that as daily production of cortisol is increased, the free cortisol filtered and not reabsorbed or metabolized in the kidneys will be increased. They noted that current research has shown that many patients with mild Cushing’s syndrome do not have elevations of urine-free cortisol, “making it a poor screening test for this condition.â€
The low-dose dexamethasone suppression test relies on the concept that the correct dose of dexamethasone will suppress ACTH, and cortisol will release in normal patients while patients with corticotroph adenomas will not suppress below a specified cut off. Raff and Findling noted that because of the significant variability of the biological behavior of corticotroph adenomas, research has shown that neither the overnight 1-mg dexamethasone suppression test nor the two-day low-dose dexamethasone suppression test appears to be reliable using the standard cutoffs for serum cortisol.
According to Raff and Findling, there is no diagnostic test used in the evaluation of Cushing’s syndrome that performs better than the late night/midnight salivary cortisol method. The concept is based on the fact that patients with mild Cushing’s syndrome fail to decrease cortisol secretion to its nadir at night. However, they still acknowledged that many factors, such as stress, sleep disturbances and psycho-neuroendocrine may falsely elevate nocturnal cortisol secretion.
“Because each of these tests has associated false positives and negatives, a combination of these tests is often necessary for a valid diagnosis,†Katznelson said. “In the end, these tests need to be considered in the context of a history and physical examination that favors this diagnosis.â€
Lynette Nieman, MD, associate director of the Intramural Endocrinology Training Program at the NIH, agreed. “Of the three recommended tests, each is useful in certain conditions,†she said. “I try to stress that the testing should be individualized since some tests are likely to be falsely positive in some situations, eg, a woman on birth control pills is likely to have a high corticosteriod-binding globulin, which might elevate serum cortisol.â€
Ruppe said the choice between the tests should be based on patient characteristics that will allow for adequate collection of each sample. “For instance, the use of a late-night salivary cortisol measurement would be suboptimal in an individual who works the third shift and may not have an intact circadian rhythm, or the choice of a 24-hour urinary free cortisol may be suboptimal in an individual with urinary frequency or urinary incontinence.â€
Ruppe also noted that one possible improvement would be to improve standardization of the assays across different labs. “Since there is no standardization, the quality of the performance of the assay can vary across different facilities and centers,†she said.
Petrosol sinus sampling
Another controversial topic in the field is whether or not the inferior petrosol sinus should be sampled for an ACTH gradient to distinguish between Cushing’s disease and occult ectopic ACTH syndrome.
The invasive procedure has proven to be relatively safe when performed by experienced radiologists, but not all medical centers have the capability.
A woman with mild hypercortisolism, a normal or slightly elevated plasma ACTH and normokalemia has an approximately 95% likelihood of having Cushing’s disease before any differential diagnostic testing is performed, according to Raff and Findling. In contrast, a male patient with prodigious hypercortisolism of rapid onset, hypokalemia and marked elevations of plasma ACTH may be more likely to have an occult ectopic ACTH-secreting tumor.
About half of patients with ACTH-secreting microadenomas are estimated to have a normal pituitary MRI. In such situations, it is important to perform further testing, particularly an inferior petrosal sinus catheterization, to discern the presence of an ectopic ACTH-producing lesion, according to Katznelson.
“Some people would say that every patient should have it because it is the one best test for the differential diagnosis of ACTH-dependent Cushing’s syndrome,†Nieman said. “However, patients in whom data strongly suggest Cushing’s disease might forego it.â€
“In a young woman with an MRI with a definitive adenoma and high-dose dexamethasone test showing less than 60% suppression, it is reasonable to proceed with surgery,†Salvatori said. “But even the International Prostate Symptom Score is not 100% sensitive or specific.†Raff said that he disagrees with the high-dose dexamethasone test.
Fast Facts: Issues at Hand
Transsphenoidal surgery
Currently, transsphenoidal surgery is the primary treatment of Cushing’s disease associated with an ACTH-secreting pituitary tumor. According to recent studies, remission rates after transsphenoidal pituitary microsurgery range from 42% to 86%.
Raff told Endocrine Today that the most important treatment recommendation that an endocrinologist makes to a patient with Cushing’s disease is referral to a neurosurgeon with extensive experience.
“Referral to a neurosurgeon who is highly experienced in this procedure is critical,†Katznelson agreed. He noted that there have been studies demonstrating that both the degree of tumor bulk resection and rates of biochemical remission are increased for all types of pituitary tumors when the surgery is performed by a neurosurgeon with extensive experience in endonasal pituitary surgery.
“In Cushing’s disease, this is especially true,†Katznelson said. “Because the tumors in this disorder are often small, if not microscopic, the surgical strategy may require dissection through the gland. In inexperienced hands, this may result in higher rates of hypopituitarism and lower rates of biochemical cure,†Katznelson said.
“There is no doubt that the surgeon’s experience influences the success rate,†Nieman said.
Constantine Stratakis, MD, with the National Institute of Child Health and Human Development, said he agreed, and stressed the importance of confirmation of diagnosis of Cushing’s syndrome prior to a referral to a neurosurgeon.
“There is nothing worse than an inexperienced surgeon operating on a patient with Cushing’s or a surgeon operating on a patient who does not have a firm diagnosis of Cushing’s syndrome,†Stratakis said.
“Surgery offers a reasonable chance for cure in the hands of an experienced neurosurgeon,†said Amir Hamrahian, MD, a staff physician at the Endocrinology Institute at the Cleveland Clinic. “We are currently involved in two studies looking at new medications for medical treatment of patients with Cushing’s syndrome. However, surgery is still the best initial approach for those not cured,†Hamrahian said.
The future
“Medications are the future for patients with inoperable, recurrent Cushing’s syndrome,†Stratakis said, referring to pasireotide (SOM230), a somatostatin analog.
He was part of a study in 2006 examining the in vitro effects of SOM230 on cell proliferation in human corticotroph tumors. Researchers found SOM230 significantly suppressed cell proliferation and ACTH secretion in primary cultures of human corticotroph tumors. They concluded that SOM230 may have a role in the medical therapy of Cushing’s disease. Raff said he believes that clinical trials in patients with Cushing’s disease who used SOM230 were not particularly successful. Anne Klibanski, MD, director of the neuroendocrine clinical center at Massachusetts General Hospital and primary investigator of the study, commented that in vitro studies play a critical role in assessing novel targeted pituitary tumor therapies. It is only in rigorous clinical trials that the overall efficacy and risks of such therapies can be established, she suggested.
Constantine Stratakis, MD
“Microsurgical improvements will also be significant, but the major problem right now is the number of patients who are left untreated with recurrent disease,†Stratakis said. “For them, there are very few options other than irradiation, so innovative medical treatments with molecularly designed compounds or targeted to specific receptors and/or functions of the pituitary are the most important advances that I see coming in the near future,†Stratakis said.
According to James Liu, MD, assistant professor of neurologic surgery at Northwestern University Feinberg School of Medicine in Evanston, Ill., the future appears bright in the battle against Cushing’s.
“Technical advances in surgery including endoscopic pituitary surgery and pseudocapsular dissection can improve surgical outcomes,†Liu said.
Katznelson said he hopes the future will bring improved diagnostic strategies important for detecting true Cushing’s syndrome in the presence of multiple comorbidities. He noted that the ongoing research studies involving innovative medical therapeutic strategies that target the corticotroph adenoma itself, or block the effects of cortisol in the periphery, should bring new treatment options in the future.
“These studies will hopefully lead to novel medical options for this syndrome,†Katznelson said. “There have been significant advances in surgery, particularly with the development of minimally invasive, endoscopic surgery that has resulted in both improved biochemical outcomes and patient tolerability.†– by Angelo Milone
For more information:
* Aron DC, Raff H, Findling JW. Effectiveness vs. efficacy: the limited value in clinical practice of high-dose dexamethasone suppression testing in the differential diagnosis of ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 1997:82;1780-1785.
* Batista DL, Zhang X, Gejman R, et al. The effects of SOM230 on cell proliferation and ACTH secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab.2006;91:4482-4488.
* Carroll T, Raff H, Findling JW. Late-night salivary cortisol measurement in the diagnosis of Cushing’s syndrome. Nat Clin Pract Endocrinol Metab. 2008;4:344-350.
* Findling JW, Raff H. Cushing’s syndrome: Important issues in diagnosis and management. J Clin Endocrinol Metab. 2006;91:3746-3753
* Liu JK, Fleseriu M, Delashaw Jr. JB, et al. Treatment options for Cushing’s disease after unsuccessful transsphenoidal surgery. Neurosurg Focus. 2007;23:E8.
* Nieman L. The dexamethasone-suppresssed corticotropin-releasing hormone test for the diagnosis of Cushing’s syndrome: What have we learned in 14 years? J Clin Endocrinol Metab. 2007;92:2876-2878.
* Lad SP, Patil CG, Laws ER Jr, Katznelson L. The role of inferior petrosal sinus sampling in the diagnostic localization of Cushing’s disease. Neurosurg Focus. 2007:23:E2.g
ERA-NET PathoGenoMics recognises outstanding PhD theses
Last Updated on Thursday, 25 October 2007 12:29 Written by admin Thursday, 25 October 2007 12:29
Increasingly, disease-causing microorganisms are being analysed on a genetic level in the hope of identifying critical factors that might be therapeutically applicable. European research in this area is being promoted under the roof of the ERA-NET PathoGenoMics network. During the 3rd European Conference on Procaryotic Genomics, held from 7 to 10 October in Göttingen, Germany, the network recognised three outstanding pathogenomic PhD theses. This year is the second time the prize has been awarded. The winners were selected from ten applications.
The ERA-NET PathoGenoMics was initiated in 2004 by the German Federal Ministry of Education and Research (BMBF) and is a network of 15 partners from Austria, Finland, France, Germany, Hungary, Israel, Latvia, Portugal, Slovenia and Spain. Their aim is to promote genomic research on pathogenic microorganisms (pathogenomics) taking place in Europe. It was initiated in 2004 and is one of around 70 ERA-NET networks aimed at counteracting the fragmentation of the European Research Area. The ERA-NET scheme is a funding instrument of the European Commission, first introduced in the Sixth Framework Programme. The underlying intention is to step up the cooperation in research activities carried out at a national or regional level in the member states.
For the second time, the ERA-NET PathoGenoMics has recognised outstanding PhD theses in the field of pathogenomics research. The annual prize is endowed with 2000 Euros for each winner. This year, three reseachers have been chosen from a total of ten applications: Christel Archambaud (France), Cédric Delevoye (France) and Joâo Paulo dos Santos Gomes (Portugal). The official award ceremony took place during the 3rd European Conference on Procaryotic Genomics in Göttingen, Germany, on 8 October. Following an introduction by Nicole Firnberg (Austria), the winning researchers had the opportunity to present the results of their thesis. The researchers were later presented with their awards by the French scientist Philippe Glaser (Institute Pasteur, Paris): a large petri dish with synthetic resin as imitation agar, through which the official award certificate can be seen, as well as a hard copy of the certificate rolled in a volumetric flask.
Christel Archambaud from the Institut Pasteur in Paris has focused on the analysis of a special enzyme family involved in signal transduction (phosphatases) and its role in the pathogenicity of Listeria monocytogetes, which can cause a number of deadly infections due to its sophisticated survival and reproduction strategy once it has entered a host. In her PhD thesis, Archambaud has identified a functional phosphatase (Stp) that appears to be crucial for the virulence of Listeria.
Cédric Delevoye, working at the Institute Curie in Paris, has analysed the intracellular infection cycle of Chlamydia. Chlamydia is a sneaky bacterial genus that can only reproduce from within host cells and causes chronic infections that are extremely difficult or impossible to treat. In his PhD thesis, Delevoye focussed on identifying membrane proteins that are secreted by Chlamydia pneumoniae during infection. In addition, he functionally characterised a single protein from the IncA-family that appears to be essential for cellular membrane fusion events.
Joâo Paulo dos Santos Gomes, working at the National Institute of Health in Lisbon, studied biological and genetic features of Chlamydia trachomatis serological variants to reveal their different pathogenic potential. Dos Santos Gomes identified highly polymorphic so-called pmp genes as playing a significant role in infection and transmission ability based on transcriptomic and immunoactivity analysis. Furthermore, he found recombination among strains to be a mechanism for generating Chlamydia trachomatis diversity.
Research group leaders from the ERA-NET partner countries are now invited to submit a proposal for the PhD Award 2008. Deadline for submissions is the 28 February 2008. For national contact details see www.pathogenomics-era.net
Posted under Education, Europe, Genomics & Pharmacogenomics, Grants and Awards, Press Releases | No Comments
Protected: BIT’s 4th Annual Congress of International Drug Discovery Science & Technology 2006 (IDDST-2006)
Last Updated on Monday, 10 April 2006 07:53 Written by iddst2006 Wednesday, 15 February 2006 11:14
Posted under Africa, Asia, Asia, Business and Investment, Cancer Research, Collaborations, Discoveries, Innovations and Patents, Drug-Like Compounds, Education, Europe, Events, HIV Research, Industry News, Medicinal Chemistry, New Products, News by Subject, North America, Press Releases, Reagents, South America | Enter your password to view comments.
NCCU’S BRITE PROGRAM TO RECEIVE LIBRARY WITH 350,000 COMPOUNDS FROM BIOGEN IDEC
Last Updated on Monday, 6 February 2006 04:50 Written by admin Monday, 6 February 2006 04:50
DURHAM, N.C. — DURHAM, N.C. – North Carolina Central University (NCCU) (Durham, NC) has entered a material transfer agreement with Biogen Idec, a global biotechnology leader, that would provide its students with access to a 350,000 compound library.
“The addition of this compound library aids the establishment of high throughput screening core facility and furthers the BRITE’s effort to collaborate with the other research organizations at the Research Triangle Park,†said Li-An Yeh, director of BRITE.
In this agreement, Biogen Idec has agreed to grant NCCU a worldwide, royalty-free, non-exclusive license to use a chemical collection of approximate 350,000 compounds at the Biomanufacturing Research Institute and Technology Enterprise (BRITE) as a research tool in its drug discovery and chemical genomic research.
“This should be an extremely valuable resource to NCCU students,†said Juan Torres, Ph.D., director of Quality for Biogen Idec and member of the leadership team at the company’s Research Triangle Park facilities.
“The availability and quick access to these data will provide students with the most current information on a wide range of chemical compounds that will promote discovery and research within the BRITE initiative.â€
Biogen Idec supports several statewide biotechnology training initiatives and has been involved with the Biomanufacturing and Pharmaceutical Training Consortium (BPTC) since its inception. BRITE is a component of the BPTC effort.
BRITE is in the process of establishing research activities toward biomanufacturing, drug discovery and related research. The mission of BRITE is to train students at the B.S.; M.S. and Ph.D. levels to work in the biotechnology and drug industries in North Carolina.
About Biogen Idec: Biogen Idec, which operates facilities in Research Triangle Park (RTP) with more than 560 employees, creates new standards of care in oncology, neurology and immunology. As a global leader in the development, manufacturing, and commercialization of novel therapies, Biogen Idec transforms scientific discoveries into advances in human healthcare. For product labeling, press releases and additional information about the company, please visit www.biogenidec.com.
Posted under Collaborations, Education, North America, Press Releases | No Comments
CHEMAXON SUPPORTS OPEN SOURCE CHEMICAL INVENTORY APPLICATION FOR UNIVERSITIES
Last Updated on Monday, 14 November 2005 01:37 Written by admin Monday, 14 November 2005 01:37
November 14th, 2005, Budapest, Hungary: ChemAxon, a software solutions provider for life sciences, announced the free provision of licenses for university users of an open source chemical inventory web application provided by Chemicalinventory.org.
Chemicalinventory.org is an open source project initiated by Dann Vestergaard and Claus Stie Kallesoe as a thesis project at their Post Graduate IT Diploma studies. Dann Vestergaard has experience as a LIMS supporter in a Danish Pharmaceutical Company but is now a full time programmer. Claus Stie Kallesoe is trained as a Medicinal Chemist and has been working with Discovery Informatics in a Danish Pharmaceutical company since 2000.
Chemicalinventory is a web application that manages the chemical stock in a laboratory-, production- or other facilities, where chemicals must be safely stored, easily found and tracked. This inventory solution is relevant to any facility which stores chemicals and is currently (since 2003) productive at The Danish University of Pharmaceutical Sciences with 70 users.
The structure input, search and visualization components of Chemicalinventory are provided by ChemAxon’s Marvin editor and viewer and JChem Base chemical search and database management tools. As a developer toolkit, with a full application programming interface (API), these tools are optimal for integrating into larger solution applications where ongoing development is a key to the application utility.
ChemAxon’s support for the chemical inventory application allows university users to receive free licenses to enable the application in their laboratories. The free provision to universities is a part of ChemAxon’s ‘Powered by Academic Package’ program where any educational establishment can receive licenses and support for all ChemAxon products at no charge. Launched last year the program has so far attracted over 270 participants. For more information or for applying to license ChemAxon’s toolkits for Chemicalinventory or your academic teaching or research please visit http://www.chemaxon.com/forum/ftopic193.html
About Chemicalinventory.org
To find out more, download or join the development of Chemicalinventory please visit http://www.chemicalinventory.org or visit the SourceForge.net location at http://sourceforge.net/projects/chi
About ChemAxon
ChemAxon is a leader in providing Java based chemical software development platforms for the biotechnology and pharmaceutical industries. With core capabilities including structure visualization and management, property prediction, virtual synthesis, screening and drug design, ChemAxon focuses upon active interaction with users and core portability to create powerful, cost effective cross platform solutions and programming interfaces to power modern cheminformatics and chemical communication. For more information please visit http://www.chemaxon.com
Posted under ChemInformatics, Education, Europe | No Comments
Southern Research Institute Announces Joint Drug Discovery Program With Schering-Plough to Seek Novel Drug Compounds
Last Updated on Wednesday, 18 May 2005 06:13 Written by admin Monday, 9 May 2005 10:01
BIRMINGHAM, Ala., May 9 /PRNewswire/ — Southern Research Institute today announced that it has entered into a joint collaborative research program with Schering-Plough Corporation (NYSE: SGP – News) to discover novel compounds as potential new products to treat infectious disease.
Building on leads generated from Southern Research’s proprietary compound repository, scientists from both companies will interact closely as a drug discovery team in a lead expansion and optimization program. Southern Research Institute will share in intellectual property and receive milestone payments gained from the efforts.
“We have conducted drug discovery work for decades through self-funded research and various government contracts and grants, and have been successful,” said John A. Secrist III, Ph.D., vice president of the Drug Discovery Division at Southern Research. “We welcome this opportunity to work with Schering-Plough, a world leader in the discovery and development of innovative therapies. We will be able to combine the strengths of two successful scientific teams in drug discovery with a singular focus to bring new drugs to market to treat unmet medical needs.”
Southern Research has a proven track record in the early discovery and synthesis of anticancer drugs. Its medicinal chemists have discovered and synthesized six of the FDA approved cancer drugs now on the market with Clofarabine being the most recent to win approval in late 2004. The company also creates and tests drugs for neurodegenerative disorders and infectious diseases, including HIV, Hepatitis, Herpes, Tuberculosis, SARS, Hantavirus, Avian influenza and West Nile virus.
“While our organization is unique in the drug discovery and development environment we have created, all of our efforts are focused on finding new compounds that show promising activity against disease targets, and doing what’s necessary to get those drugs to market,” said David R. Harris, director of Drug Discovery business development at Southern Research Institute. “Being able to work with Schering-Plough complements their strategic efforts and expertise.”
About Southern Research Institute
Southern Research is a diversified network of collaborative centers for scientific discovery and technology development. Southern Research is a recognized leader in leveraging more than 60 years of achievement to create innovative solutions for public and private sector clients in the pharmaceutical, health, biotechnology, chemical and biological defense, homeland security, automotive, environmental, energy, aerospace and engineering industries. Southern Research is based in Birmingham, Ala., with other major research operations in Frederick, Md. and Research Triangle Park, NC. For more information, visit www.southernresearch.org .
Media Contact
Rhonda Jung, Southern Research Institute, 205-581-2317, jung@sri.org
Source: Southern Research Institute
Posted under Collaborations, Drug-Like Compounds, Education, North America, Research Projects | Comments Off