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By W. Urkrass. Amherst College. 2018.

Dysopyramide crosses the placenta readily arimidex 1 mg without a prescription, with fetal levels approximately half those of the mother (Rotmensch et al buy arimidex 1mg with amex. The drug was embryo- toxic in laboratory animals when given at several times the human dose, but no pattern or specific malformations were noted (data from the manufacturer’s insert). Disopyramide use during the third trimester has been associated with premature onset of labor (Leonard et al. Bretylium This drug is primarily indicated for life-threatening ventricular arrhythmias, such as ven- tricular tachycardia and ventricular fibrillation. Bretylium was reported to be ‘without effect’ in one rat study published by West (1962). Amiodarone This drug is used primarily to treat life-threatening ventricular arrhythmias (e. Amiodarone has limited ability to cross the placenta, with newborn concentrations reaching only 10–25 percent of maternal serum levels (Rotmensch et al. Of six pregnancies exposed to amiodarone after 10 weeks ges- tation, hypothyroidism (n = 2) and small size for gestational age (n = 4) was observed (Magee et al. Learning disabilities were unusually frequent in two small series of children exposed to amiodarone during gestation (Bartalena et al. When administered chronically during pregnancy, fetal goiter is a major risk after 10 weeks gestation. Fetal death is consistently reported in animal studies of the drug dur- ing pregnancy. A possible association between fetal cretinism has also been suggested, especially from direct fetal injection (Pinsky et al. Otherwise, the frequency of congenital anomalies was not increased among 30 infants exposed to amiodarone dur- ing the first trimester (Bartalena et al. Mexiletine Similar in action to lidocaine, mexiletine is a local anesthetic type of antiarrhythmic agent (Zipes and Troup, 1978). Mexiletine is used primarily to treat ventricular arrhyth- mias (ventricular tachycardia, premature ventricular contractions). No studies of con- genital anomalies in infants exposed to mexiltene have been published. A few anecdotal case reports suggest no adverse effects on the fetus or on labor, but the importance of such observations is not clear. Mexiletine was not teratogenic in various laboratory ani- mals (data from the manufacturer’s insert). Cord blood concentrations of this drug were similar to maternal levels, and therapeutic levels may be found in breast milk (Timmis et al. However, breastfeeding is not contraindicated when the mother is using mexiletine (American Academy of Pediatrics, 1994). Verapamil is used to transplacentally treat fetal supraventricular tachycardia (Klein and Repke, 1984; Rey et al. Verapamil should be used with caution in pregnant patients because it might reduce uterine blood flow by 25 percent or more (Murad et al. Importantly, 10–20 percent of neonates who received this drug intraveneously for supraventricular tachycardia and congestive heart failure devel- oped cardiac depression and cardiac arrest (Kleinman and Copel, 1991). Therefore, ver- apamil is not recommended for use in infants of less than 1 year (Garson, 1987). Verapamil might have adverse effects in the fetal heart, especially in the presence of heart failure and hydrops (Shen et al. Among 33 infants exposed to verapamil in the first trimester, no increase in congenital anomalies was reported (Magee et al. Verapamil is not contraindicated in breastfeeding mothers (American Academy of Pediatrics, 1994). Propranolol Propranolol is a beta-adrenergic blocker used to treat supraventricular and ventricular tachycardias, hypertension, hyperthyroidism, and migraine headaches. It is also used in the intrauterine treatment of fetal arrhythmias (Bhagwat and Engel, 1995; Eibeschitz, 1975). The major- ity of this information is derived from the treatment of hypertension during pregnancy. Nonetheless, no controlled human teratology studies of propranolol have been published. The drug was not teratogenic in at least two animal studies (Fuji and Nishimura, 1974; Speiser et al. Adverse fetal effects have been reported with the use of propranolol during pregnancy. Intrauterine growth retardation and use of propranolol were associated in one study (Pruyn et al.

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Loose Face Powders This type has declined in popularity in favor of pressed face powder products arimidex 1 mg without prescription. The smoothness of loose face powder can be enhanced by use of the aforemen- tioned texture enhancers cheap 1mg arimidex free shipping. In the manufacturing process, all ingredients except the pearls, if required, are combined in a stainless steel ribbon blender. Mixing time can be as long as 1 or 2 h, depending on the size of the batch and evenness of the color. Perfume, if required, is slowly sprayed into the batch, and blended until homogeneous. Color adjustments are made, if necessary, in the ribbon blender and the batch is repulverized. Pressed Face Powders Pressed face powders are more popular than loose powders because of their ease of application and portability. The basic raw materials are the same as loose powder except that a binder must be used to press the cake into a tin-plate godet. If water-based binders are used, aluminum godets should be considered to prevent corrosion. The properties of a binder are is follows: provides creaminess to the powder, aids in compression and adhesion, develops colorants, enhances water- resistance and pick-up and deposit. If the binder level is too high, it may be difficult to remove the powder with a puff. Also, high levels may lead to glazing of the powder surface, making it waxy looking, with little or no pay-off. Fatty soaps, kaolin, polyethylene, teflon synthetic wax and calcium silicate are some of the binder systems used. Silicone-treated pigments have given rise to pressed face powders that may be used wet or dry. When a wet sponge is applied to the cake, no water penetrates the cake; the water is repelled. When formulating pressed powders, care must be taken so that the raw materials used do not corrode the godets or attack the plastic packaging materials. The manufacture of pressed pow- ders, including the mixing and color-matching process, is similar to loose pow- ders. Sometimes the powder mix is pulverized without binder and then again 294 Schlossman after its addition. Pearls are usually added during the blending process and prefer- ably without the milling operation, which can damage the pearl. If milling a batch containing pearl becomes necessary, it should be done with the mill screen removed. Powder pressing is often more successful if the powder is kept for a few days to allow the binder system to fully spread, especially when pearls are present. The pressures used and the speed of pressing depends on the characteris- tics of the individual formulation and the size of the godet. Powder Blushers The attributes of blushers are as follows: (1) add color to the face; (2) give more dimension to the cheekbones; (3) harmonize the face-balance between eye makeup and lipstick; (4) create subtle changes in the foundation look when lightly dusted over the face. Pressed powder blushers are similar to face powder formula- tions, except that a greater range of color pigments are used. The three basic iron oxides and one or more of the lakes are used to achieve various blusher shades. Care should be taken than only nonbleeding pigments be used to avoid skin staining. Pressed powder rouges were once popular and contained high levels of colorants (10–30%). Usually they are applied from the godet with the finger so that glazing may frequently occur if the rouge is improperly formulated. Pressed Powder Eyeshadows Eye shadows in general have the following functions: (1) Add color and personal- ity to the face; (2) sharpen or soften the eyeball itself; (3) create the illusion of depth or bring out deep-set eyes; (4) create light and dark illusions for subtle character changes; and (5) can be used wet or dry for different illusions. The technology is similar to other pressed powder products but the permitted color range is limited. Problems of poor adherence to the skin, color matching, and creasing in the eyelid is common when the binder formulation is ineffective with the type and level of pearls used. In manufacture, formu- las with high pearl content should be allowed to settle to remove entrapped air before pressing. Decorative Products 295 Quality Assurance on Powder Products Color testing is done, where production batch and standard are placed side by side on white paper and pressed flat with a palette-knife. Bulk density is carried out on loose powder to ensure that no entrapped air is present so that incorrect filling weights are minimized. A penetrome- ter is used to determine the accuracy of the pressure used during filling. Normally, the godet is dropped onto a wooden floor or rubber matte (1–3 times) at a height of 2 to 3 ft to note damage to the cake. Glazing and payoff is done where the pressed cake is rubbed through to the base of the godet with a puff and any signs of glazing is noted.

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Sometimes purchase arimidex 1mg line, there are too many statutory exceptions and loopholes that are downright dangerous cheap 1mg arimidex with visa. For example, theophyllin is a powerful drug with a narrow therapeutic index, and is used in the treatment of asthma; blood levels should be monitored frequently. Yet, this same agent can be sold as an unregulated cosmetic when incorporated in topical formulations for the treatment of cellulite. I recommend that all interested parties read the scholarly treatise prepared by Vermier and Gilchrest, respectively (6). They argue that cosmeceuticals al- ready exist and are in fact desirable as intermediates between cosmetics and drugs and that they should continue to be regarded as cosmetics. They move toward the European position and recommend that it is in the interest of manufacturers to prove the efficacy of active cosmetics. Recent papers strongly express the feelings and beliefs of major players in this field. Is it an attempt to convince the consumer that their skin care product is really a topical medicine without a proper license, or is it a genuine category that attempts to provide a mild product that has been more stringently tested than a normal skin care product? He recommends reading an official medicine leaflet as a guide to deciding what comprises a medicinal product. He considers ‘‘that the existing legal regulations are precise and clearly distinguish between cosmetic and pharmaceu- tical efficacy. They do not allow for the introduction of a new class of products such as cosmeceuticals. The piece de resistance of the cosmeceutical imbroglio is the article by Urbach (10), who states: Cosmeceuticals 7 At the moment, there is hardly a topic in the cosmetic industry as controver- sial as cosmeceuticals. From a consumer and regulatory point of view, having a separate cosmeceutical class in neither helpful, scientifically suitable or juridically necessary. The most sensible and useful service we can give the consumer legislator and manufacturer is to advise against the further use of this term (11)! He endorses the term and thinks its introduction has made it necessary to reconsider the statutory defi- nition of a drug and a cosmetic and to seek international agreements on the kinds of regulatory actions that might be enacted. It turns out that the Japanese government recognized early on the problems that were coming to the fore as a result of the cosmetic industry’s ability to create ‘‘performance’’ products that did more than beautify. It is abundantly clear that, for the sake of fair trade, a rapidly expanding international marketplace will have to come to grips with the problems presented herein. Efficacy claims of cosmetics in Europe must be scientifically substanti- ated from 1997 on. Moreover, in the United States, Europe, and Japan, different definitions of cosmetics are used. It is noteworthy that in this definition the cosmetic is not allowed to have any activity (i. The definition of a cosmetic is described in article 1 and is as follows: A ‘‘cosmetic product’’ shall mean any substance or preparation intended to be placed in contact with the various external parts of the human body epider- 9 10 Vermeer mis, hair system, nails, lips and external genital organs or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance and/or correct- ing body odours and/or protecting them or keeping them in good condition. The other 15 articles describe the following topics: overall safety requirements, controlled substances, potential ban of animal testing, inventory of ingredients, labeling, harmonization, product information requirement, procedure for adapta- tion, list of permitted ingredients, safeguard clause, and implementation. According to the pharmaceutical affairs law, the Japanese definition of a cosmetic is as follows: The term cosmetic means any article intended to be used by means of rub- bing, sprinkling or by similar application to the human body for cleansing, beautifying, promoting attractiveness and altering appearance of the human body, and for keeping the skin and hair healthy, provided that the action of the article on the human body is mild. The Japanese definition is only slightly different from the definition of a cosmetic within Europe. Both definitions allow a cosmetic to have mild activity and possess pharmaceutical activity. Moreover, in article 7a of the European cosmetics directive, which de- scribes the product information requirement, it is stated that a proof of effect should be included (2). In the United States, however, a product would be re- garded as a drug if a proof of effect was mentioned. Extensive research on the physiological activity of the skin has provided evidence that even small changes in the environment can modify the activity of skin tissue (3,4). As mentioned by Gilchrest, the Food and Drug Administration asked her to define water as a drug, when water was applied on the skin under experimental condi- tions (7). Registration of a product as a drug requires many elaborate and costly procedures; therefore, the manufacturer of a product with pharmaceutical activity would prefer to have the product registered as a cosmetic. This might mean that the pharmaceutical activity of the product is not mentioned and/or investigated, and, as a result of these confusing and old-fashioned regulatory rules, important information is not given to the public. The introduction of the term ‘‘cosmeceutical’’ enables us to classify more precisely a product with an activity that is intended to treat or prevent a (mild) skin (abnormality). In order to avoid introducing new definition criteria, we sug- gest that cosmeceuticals are only regarded as a subclass within the domain of a Definition 11 Table 1 Cosmeceuticals as a Subclass of Cosmetics (Europe and Japan) and as a Subclass of Drugs (U. In Europe and Japan, cosmeceuticals can be regarded as a subclass of cosmetics; however, in the United States cosmeceuticals can only be regarded as a subclass of drugs.

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The absorptive transport of cyclosporin A was relatively constant from day 5 of culturing (treatment with the P-gp inhibitor verapamil significantly increased absorptive permeability purchase 1 mg arimidex fast delivery, consistent with inhibition of polarized efflux mechanism) generic arimidex 1 mg mastercard. The secretory transport of cyclosporin A increased until day 17, at which time this permeability became constant. The reduced barrier function observed before day 17 is most likely due to incomplete monolayer differentiation or incomplete P-gp expression versus that observed at day 17. Caco-2 cells of lower passage numbers (*22) have been shown to have a shorter doubling time than those of higher passage number (*72), resulting in an increased number of cells per monolayer and thus an increased amount of membrane protein. However, several reports have stated that Caco-2 cells at higher passage numbers (>90) contain significantly more P-gp than those at lower passage numbers. P-gp expression in the Caco-2 cells has been shown to be stable, and this allows relatively accurate comparison of data from various monolayers as long as they represent a relatively narrow range of passage numbers. Expression of specific proteins can be induced in Caco-2 cells using simple culturing techniques. Overexpression of P-gp can also be achieved in the Caco-2 cell line by culturing with vinblastine, verapamil, and celiprolol (358,359). No morphological differences were noticed for vinblastine cultured cells with respect to appearance, formation of tight monolayers, and the corresponding transepithelial resistance (359). Both have been used to follow the passive diffusion of compounds across monolayers. The model’s considerable advantages have led to it being increas- ingly used as the model of choice to screen for P-gp efflux liability. These cultured cells have been shown to retain many morphological and biochemical properties of their in vivo counterparts, including distinguishable luminal and abluminal membrane domains that are functionally and biochemically distinct (371–381). The comparable leakiness of the system can also make it difficult to quantify differences in transport that may be mediated by transporter activity. Several examples have demonstrated the usefulness of this system to study polarized efflux via P-gp. For example, the influence of P-gp expressed in brain capillary endothelial cells on the transport of cyclosporin A (388,389), vincris- tine (381), protease inhibitors (amprenavir, saquinavir, and indinavir) (245,390), rhodamine 123 (211,383), opioid peptides (211,391,392), and the b-blocking agent bunitrolol (393) have all been determined using this system. Experimental Methods Used with Tissue Culture Transport Models to Study P-gp Efflux The use of appropriate experimental design can provide definitive evidence that P-gp-mediated efflux is altering the transport of a compound and can provide further mechanistic information regarding the transport of a compound. Recently it has been appreciated that P-gp efflux can be a potential source for drug interactions and in vitro experimentation can be very helpful to understand potential liability. The techniques described in this section can be used with any tissue culture transport model. Transport across cell monolayers can be easily determined using a bicameral system, such as the 1 Transwell system, in which the compartments are separated by the polarized cell monolayer (attached to a porous filter support). One of the most significant advantages of this experimental system is that the appearance rather than the disappearance of the compound can be easily quantified to yield a permeability value. Comparison of the per- meability values provides a true measure of how P-gp affects the transport of the substrate across polarized epithelium and correctly identifies if the transport is subject to P-gp-mediated efflux activity (vs. This experimental format allows an assessment of how significantly P-gp efflux attenuates or enhances absorptive versus secretory transport, respec- tively (394). Another well-established metric used to identify P-gp substrates is the efflux ratio, in which secretory permeability is compared with absorptive permeability. An efflux ratio greater than one can imply apically directed transport polarity, suggesting that the compound is a substrate for efflux transport (395). It is important to note that apically directed transport as determined by efflux ratio does not provide unambiguous evidence that P-gp is responsible for the efflux of the compound (transporters other than or in combination with P-gp may be respon- sible for transport polarity). Although the efflux ratio can, under the proper experimental construct, be useful to identify The Role of P-Glycoprotein in Drug Disposition 397 P-gp substrates, it does not quantify the functional activity of P-gp and furthermore cannot be used to understand how P-gp affects absorptive or secretory transport (206,394,396). For example, although digoxin and rhodamine 123 have similar efflux ratios, P-gp affects these compounds in much different ways; P-gp efflux affects digoxin absorption, but not rhodamine 123 absorption, and affects rhod- amine 123 secretion greatly but digoxin secretion modestly (396). There is one major caveat of using the tissue culture transport experiment to study P-gp efflux that cannot be overlooked—P-gp efflux is not directly determined in this experiment. Rather, the effects of P-gp-mediated efflux activity and changes to this activity are inferred from the resulting overall transport data. Particularly with regards to substrate identification, there is the potential for false negatives. For a compound to be affected by P-gp-mediated efflux, it must reach P-gp’s binding site that is within the cell. Compounds with poor membrane (transcellular) per- meability are not likely to be identified as substrates (395,397). Conversely, compounds with very high passive membrane permeability can saturate P-gp efflux at low micromolar concentrations and are often not identified as substrates (206,395,397). The tissue culture transport study is a powerful tool, but the reasons listed above make it an absolute necessity to incorporate proper controls while performing and making conclusions from these studies. Increasingly, efforts are being made to quantify the inhibitory potency of new molecular entities against P-gp-mediated efflux using interaction studies performed in vitro.

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