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Microdose studies use very low amounts of the pharmaceutical ingredient or bulk drug. "The low amount of bulk drug clearly translates to a low cost. It also means low usage of experimental animals, and low environmental and human exposure risk. But most importantly for drug companies is the aspect of low costs, " said Pfizer's Sarapa. "If we can kill the compound at an early stage based on human microdosing, before the very costly business of pharmaceutical scaleup has been initiated, it translates into savings anywhere between $500, 000 and $2.5 million, depending on how expensive the compound is to make. There are very direct, very real savings. "Otherwise, if you continue the development of this compound, " Sarapa added, "you would have to scale up the manufacturing to a point where you would be utilizing raw materials and chemical plants and numerous outsourced partners. Equally important, you would start utilizing this newly synthesized compound for new tests that eventually prove to have poor PK properties in humans. If you do microdosing and realize those poor properties sooner, then all of that subsequent cost and subsequent studies will be unnecessary and you can save both in human resource and the cost." Microdosing studies also can be completed more quickly than traditional phase I studies. For example, Xceleron recently worked with a company that carried out three human microdose studies on a compound within a 12-month period. "They did the studies in sequence, rather than in parallel, " Garner said. "They got the microdose data, decided that the molecule could be improved in some way, improved it, repeated the process, got some more microdose data and then improved the molecule a little more. They ultimately got a molecule which they think has the optimum pharmacokinetic characteristics. If you were to do classiFebruary 2005.

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Phia, Pa ; , or a matching placebo also provided by Wyeth Pharmaceuticals ; . Randomization was determined using a permuted block algorithm that was stratified according to age group and clinical center site with implementation by the WHI Clinical Coordinating Center CCC ; Fred Hutchinson Cancer Research Center, Seattle, Wash ; . Participants were given their next supply of study pills semiannually. They returned annually for clinic visits and were contacted semiannually for safety and outcomes ascertainment.

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It is much easier to obtain an ejaculate when an estrual bitch is present; therefore owners should be asked to bring in teasers when appointment are made. Alternatively, a non estrous bitch of the same breed or size may be used. A commercially available pheromone methyl paraben "Eau d'estrus, Synbiotics corporation phone 18584513771, fax at 18584515719 ; may be used to stimulate the male but we have no experience in its use. It is sometimes very difficult to collect semen if no bitch is available at all can it can be done. Optimally, the male and female are brought together on leashes in a quiet room with nonslip flooring. As the dog sniffs at the bitch's vulva or mounts her, the collector quickly moves the prepuce back, behind the bulbus glandis and directs the tip of the penis into the AV, held in the left hand. Once the artificial vagina is slipped onto the penis, the right hand is used to hold the artificial vagina onto the penis while exerting firm pressure around the back of the bulbus glandis. Once this occurs, the dog will usually show pelvic thrusting and normal ejaculation. An AV is certainly not essential to collect semen from dogs. Excellent ejaculates can be obtained by hand collection alone. If a gloved or bare hand is used instead of an AV, the dog is masturbated rapidly for a few seconds until he gains a full erection. In the process, the prepuce is slipped behind the bulbus glandis. Masturbation ceases and the hand held behind the bulbus glandis using very firm pressure, until ejaculation is complete. The other hand is used to hold a plastic bag over the end of the penis. Almost any warm receptacle can be used to collect the semen but most commonly sterile "Whirlpak" bags are used. Syringe casings and other hard objects should be avoided as the penis is very easily traumatised during collection and substantial bleeding may occur into the ejaculate. This does not seem to decrease fertility in dogs Cf horses ; but it interferes with semen evaluation and of course, alarm owners. Semen can be collected when the bulbus glandis expands within the prepuce but some dogs object to this. Therefore, it is usually best to be sure that the bulbus glandis is out of the prepuce before it expands. The reader can see therefore than the term "masturbation" is somewhat misleading. Most of the contact time consists of pressure exertion behind the bulbus glandis; a process identical to that used with an artificial vagina! Ejaculation occurs intermittently over a variable period, perhaps five to 15 minutes, usually just long enough to deprive the collector squatting on the floor ; of all blood flow and feeling to the legs. If pressure is maintained firmly around the bulbus glandis, pulsations can be palpated in the urethra. The anus will also be observed to contract in a rhythmic fashion. The dog may stop ejaculating for several minutes then pulsations will resume. Initially, a few drops one to 3 ml ; clear to slightly cloudy pre sperm fraction are ejaculated, followed by a whitish spermrich fraction 0.1 to 6.0 ml ; but most often these fractions are mixed and only a homogeneous light greyopalescent ejaculate is obtained. The collector should try keep one hand around the collection vessel to keep it near body temperature. This is easiest when a plastic bag is used as a collection vessel. Soon after the dog begins to ejaculate, he will often lift his hind limb as though attempting to step into the rumptorump position that occurs during natural breeding. If this is observed, the collector should allow the dog to step over his her arm so that the penis then extends out caudally from the dog. Soon the clear, third fraction of the ejaculate mostly prostatic fluid ; is ejaculated increasing the volume to as much as 60 ml. If the semen is being collected for artificial insemination as well as evaluation, enough prostatic fraction is collected to bring the total volume to three to 10 ml large numbers of sperm are not lost in the insemination process and the insemination volume is comfortable to work with. Frequently, only a few ml of semen are collected but total sperm numbers, not semen volume, is what is important in A.I. After collection is complete, the male is observed until his erection subsides. Paraphimosis may occur following collection, so the dog must never be kennelled or sent home until the penis is completely inside the prepuce. To prevent paraphimosis, one should lubricate the preputial opening liberally after semen collection and gemfibrozil and diovan, for example, diovzn 160mg. 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