Penicillins are the most frequently sold antibiotics for treatment of broilers [34] and even though cephalosporins and carbapenems are not registered for use in animal production provera 10 mg sale womens health daily magazine, due to their high effectiveness their veterinary use buy discount provera breast cancer awareness bracelets, including broilers, cannot be ruled out. To prevent off-label use of ß-lactams in animal breeding and thus to limit the dissemination of bacterial resistance, an effective control strategy for ß-lactam usage in food-producing animals is needed including penicillins, cephalosporins and carbapenems. However, off-label use of cephalosporins should be restricted because of the risk of the development of bacterial resistance. Therefore the use of cephalosporins should be monitored and thus detection of these compounds at levels as low as reasonably possible is mandatory. Ceftiofur and cefapirin are known to rapidly metabolise after intramuscular administration. Based on the results a new approach was developed for the analysis of the total residue levels of ceftiofur and cefapirin in kidney. To study the applicability of this new method it was compared to routinely applied methods for the analysis of ceftiofur in poultry tissues. Other ß-lactam antibiotics were included in the newly developed procedure which resulted, after some alterations of the method, in a multi-ß-lactam method that includes penicillins, cephalosporins and carbapenems. Newly identified degradation products of ceftiofur and cefapirin impact the analytical approach for the quantitative analysis of kidney Abstract This section describes the research on the degradation of ceftiofur and cefapirin at physiological temperatures in kidney extract and in alkaline and acidic solution, conditions that regularly occur during sample preparation. A slight instability of cefapirin and desfuroylceftiofur was observed at elevated temperatures. Ceftiofur and cefapirin degraded immediately and completely in an alkaline environment, resulting in inactive degradation products. Ceftiofur and cefapirin also degraded immediately and completely in kidney extract resulting in both formerly reported metabolites as well as not previously reported products. Our research shows that conditions often occurring during the analysis of ceftiofur or cefapirin result in rapid degradation of both compounds. From this it is concluded that underestimation of the determined amounts of ceftiofur and cefapirin is likely to occur when using conventional methods for the quantitative analysis of these compounds in tissue. Therefore, a new approach is needed for the analysis of both compounds including their degradation products. Because cephalosporins are highly effective antibiotics in the treatment of bacterial infections of the respiratory tract [10], the common use of cephalosporins in veterinary practice is expected. An effective monitoring of 202 Chapter 5 cephalosporin use in animal breeding is mandatory to prevent excessive use, which will contribute to the emergence of bacterial resistance. In monitoring food products, it is not clear that all relevant metabolites and degradation products, such as those produced by the degradation of ceftiofur and cefapirin during sample preparation, are taken into account when current methods are used to test for ceftiofur and cefapirin in tissue samples. The main causes of such degradation can be (1) the use of elevated temperatures, (2) the presence of tissue extract [43] and (3) an acidic or alkaline environment [44]. If degradation caused by these three aspects is not taken into account it is possible that ceftiofur and cefapirin residues are underestimated. Ceftiofur and cefapirin are known to rapidly metabolise after intramuscular administration. Cephalosporin multi-methods that include both ceftiofur and cefapirin are lacking, although methods to detect cetiofur and cefapirin in tissue separately or in combination with a limited number of other cephalospirins have been reported [35,43,45-47]. This method is not very robust so the procedure has to be closely followed to obtain good results and it is limited to the analysis of a few cephalosporins and thus unsuitable as a multi-method. The degradation processes possibly occurring after this time are not taken into account. Accurate mass determination and calculated elemental composition data can be used for structure elucidation. The new identified products indicate that currently applied methods are likely to underestimate the residue levels of ceftiofur and cefapirin found in kidney samples. Furthermore, this research resulted in a new approach for the quantitative analysis of ceftiofur, cefapirin and other cephalosporins in tissue. Preparation of kidney extract A blank bovine kidney sample was defrosted and homogenised at room temperature, after which 5 g was transferred to a 50 mL test tube. The gradient (mobile phase A, 0,05 % ammonia in water, pH adjusted to 8 with acetic acid; mobile phase B, 0. The instrument was operated in the positive W-mode (resolution ≥ 10,000) and was calibrated spanning a range of 90 to 1050 using a solution of sodium formate in 2- propanol to obtain a mass error below 5 ppm. A solution of 1 µg mL leucine-enkephalin in -1 water/acetonitrile (1:2), infused at a flow rate of 10 µL min was used as a reference, resulting in a lock mass of m/z = 557. The reference scan frequency was set at 10 scans, the reference cone voltage at 20 V and the reference aperture 1 voltage at 8. Stock solutions were diluted to 200 ng mL in water of which 20 mL was transferred to a test tube and placed into a Julabo 25 water bath (Julabo, Seelbach, Germany) set at a temperature of 37 °C. Stock solutions were diluted in each of the phosphate buffer -1 solutions to obtain 10 µg mL solutions at different pHs in the range of 2. After 0, 30, 60, 120 and 180 minutes at room temperature, 100 µL of these solutions was combined with 4. The compounds were considered unstable when the peak intensity decreased over 10 %. A separation was established using an X-Bridge C18 analytical column, 150 x 3 mm, 5 µm (Waters). Both solutions and pure methanol were diluted tenfold in water to obtain solutions containing 10 % methanol after which 2 mL was transferred to different test tubes in duplicate, resulting in two identical sets, each set consisting of one blank tube, one containing 100 µg cefapirin, and one containing 200 µg ceftiofur. The different fractions of each of the 20 injections were combined in test tubes resulting in 4 mL fractions. This software aligned chromatograms of the blank solution with the chromatograms of the ceftiofur and cefapirin spiked solutions, after which the differences between the two sets of chromatograms were determined. This procedure resulted in chromatograms containing accurate mass full scan data showing mainly degradation products. For each degradation product, the most likely molecular formulas was selected, using the elemental composition option in MassLynx 4. The molecular formula of the degradation products was determined with a high certainty because ceftiofur and cefapirin contain sulfur atoms having a very specific isotope [M+2] and several nitrogen atoms. Before Fourier transformation and phasing, a 1/3 shifted sine squared window multiplication was applied and a zero-filling to 128 K data points were applied. Antimicrobial activity becomes visible as a zone of growth inhibition around the paper disk. Kinetics The kinetic experiment was carried out for ceftiofur and cefapirin separately. Nothing further was added to the first test tube, 5 mL kidney extract was added to the second test tube, 125 µL 25 % ammonia was added to the third test tube and 5 mL kidney extract and 125 µL 25 % ammonia were added to the fourth test tube. From the data obtained, the formation of the degradation products was studied in a qualitative way using the MetAlign Software. In the figures displaying kinetic results the highest signal obtained is set at 100 % and all other signals are related to this without suggesting a quantitative relation exists. The corresponding retention times and molecular formulas are presented in table 5.

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Thus the rate- limiting step for systemic absorption of drugs from intravaginal creams purchase provera with a visa women's health clinic stephenville tx, inserts and tablets is often dissolution within the vaginal fluid cheap 5 mg provera visa menopause belly fat, particularly for poorly soluble drugs. Obviously, the type of dosage form affects the rate of dissolution; for example, a drug which is already dissolved in an aqueous vaginal gel will be more rapidly absorbed than a drug which is in solid form within a vaginal tablet preparation. The effective area of contact Although the area of the vaginal cavity is approximately 60 cm, the formulation will influence the size2 of the area over which the drug is deposited. The vehicle should facilitate even distribution of the drug throughout the vagina, rather than concentrating it in one spot. Factors such as the hydrophilicity and viscosity of the vehicle will determine how well it spreads through the vagina. Contact time The formulation will also influence the extent of the contact time the drug has with the absorbing surface of the vaginal epithelium. Typical delivery systems such as foams, gels and tablets are removed in a relatively short period of time by the self- cleansing action of the vaginal tract. New bioadhesive gel delivery systems are being developed to prolong contact time with the absorbing surface and are described below. Concentration The rate of absorption via passive diffusion processes (transcellular and paracellular) can be increased by increasing the drug concentration in solution at the absorbing surface (see Section 1. For systems intended for prolonged administration, a highly saturated formulation will also ensure that sufficient drug is present to ensure sustained drug delivery throughout the intended time of application. However, care must be taken, as high local drug concentrations over extended periods of time may also cause severe local irritation or adverse tissue reactions. A brief overview of both the advantages and disadvantages of vaginal drug delivery is given below. However, it2 is much smaller than that offered by the nasal (150 cm ), rectal (200–400 m ), pulmonary (75–700 m ) and3 2 2 intestinal (200 m ) routes. In contrast to the oral route, this route also avoids degradation in the intestinal wall or the liver, prior to the drug reaching the systemic circulation. Reduced first-pass effects after vaginal application of estrogens, progestogens and prostaglandins have all been reported in a number of studies. Permeability The vagina demonstrates a relatively high permeability to many drugs, particularly during the late luteal and early follicular phases of the menstrual cycle. Ease of administration Intravaginal dosage forms are relatively easy to administer and offer the feasibility of self-administration. Patient compliance is generally good, particularly if no leakage or staining occurs. Prolonged retention Prolonged retention of the drug is possible, if the appropriate delivery system such as vaginal silicone ring is used, thereby allowing a reduction in the dosing frequency. Alternative when the oral route is unfeasible The vaginal route may be appropriate in certain situations where the oral route is unfeasible, such as: • patients with nausea and vomiting; • patients with swallowing difficulties; • drugs that cause gastric irritation; • drugs that are unstable in the gastrointestinal fluids; • drugs that undergo extensive first-pass effects in the gut wall or liver. Zero-order controlled release Vaginal drug delivery offers the potential to achieve zero-order controlled release over a controlled period. Adverse effects The relatively low amount of fluids bathing the vaginal mucous membranes means the tissue is prone to adverse reactions, such as local irritation, caused by vaginal devices. Similarly, locally irritating or sensitizing drugs must be used with caution in this route. Furthermore, materials used in vaginal preparations should be sterilized and not act as a growth medium for the proliferation of pathogenic microorganisms, bacteria, fungi, and protozoa. Hormone-dependent changes Cyclic changes in the reproductive system mean that large fluctuations in vaginal bioavilability can occur. Cyclical changes in the vaginal epithelium include changes in the thickness and porosity of the vaginal epithelium, the amount and pH of the vaginal fluids and the degree of enzymatic activity present. Furthermore, estrogen therapy and steroidal contraceptives influence the vaginal fluid, epithelial thickness and vascularity, which also contributes to a lack of reproducibility in the vaginal absorption of drugs. This lack of reproducibility constitutes a major problem associated with vaginal drug delivery and, for drugs with a narrow therapeutic index, such variations may be unacceptable. Leakage The bulbocavernosus muscles which surround the orifice of the vagina are not usually strong enough to retain vaginal preparations in the same way as the anal sphincter retains rectal suppositories. Slipping-out or leakage may occur, particularly in the case of preparations involving a relatively large volume of liquid or semisolid. Life-cycle constraints The vagina is the final part of the internal female genitalia, the parturient canal, and also serves as a passage for the outflow of cervical fluids and the menstrual flow. Menstruation, intercourse, pregnancy and delivery, and other anatomical or physiological changes in the life cycle of women must also be taken into account when the timing and effectiveness of drug application are being considered. Applicability constraints No matter what degree of optimization can actually be achieved via this route, it must be remembered that vaginal delivery is only applicable to approximately 50% of the population. Thus it may be that the true potential of this route lies in the treatment of female-specific conditions, such as in the treatment of climacteric symptoms of the menopause etc. However more recently, the vaginal delivery of estrogens, progesterones and prostaglandins has been considered in term of their systemic, as opposed to merely local, delivery. Current technologies in vaginal drug delivery are increasingly concerned with the systemic delivery of these agents and commercial preparations are now available: 11. This risk can be eliminated by treatment with a progestational agent for up to 14 days a month. These limitations can be overcome by the vaginal administration (tablets, suppositories, gels) of progesterone. Vaginal administration gives higher plasma levels than the oral route and levels are sustained for a longer time (Figure 11. Estrogens are also subject to extensive first-pass effects (it has been shown that these first-pass effects occur predominantly in the intestinal wall, rather than in the liver) after oral administration. Again, vaginal administration of estradiol results in higher bioavailability than via the oral route (Figure 11. A number of different types of vaginal rings containing various progesterones and estrogens have been investigated as a steroidal contraceptive since the mid-1970s, the most successful being a Silastic toroidal- shaped ring. This is designed for insertion into the vagina and positioned around the cervix for 21 days, in order to achieve a constant plasma progestin level and cyclic intravaginal contraception. Although the device is successful in achieving the prolonged release of levonorgestrel, irregular bleeding is a major drawback associated with its use. In postmenopausal women with symptoms of urogenital aging, the vaginal ring gives significantly better, or equal, improvements of vaginal mucosal maturation value and restoration of vaginal pH levels than estradiol—containing vaginal pessaries or conjugated estrogen vaginal creams and is significantly more acceptable. Vaginal administration of progesterone is associated with a “first-uterine-pass effect”, i. Using a human ex vivo uterine perfusion model, the vaginal administration of radioactive progesterone was shown to result in the progressive migration of [ H]3 progesterone into the uterus, where it reached high concentrations in both the endometrium and the myometrium. Furthermore, vaginal administration of micronized progesterone has been shown to enhance progesterone delivery to the uterus by about 10-fold in comparison to im injection, despite the markedly higher (about 7- fold) circulating drug concentration achieved with im injection. Uterine selectivity after vaginal 288 administration has further been observed for both danazol and the β-agonist terbutaline and the vaginal-to- uterine delivery of misoprostol is currently being investigated for the reliable termination of early pregnancy (see below). Hence considerable evidence has accumulated demonstrating that the vaginal route permits targeted drug delivery to the uterus. This phenomenon opens new therapeutic options for the administration of compounds whose primary site of action is the uterus, thereby maximizing the desired effects, while minimizing the potential for adverse systemic effects.

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