R. Jorn. Lock Haven University.

The elimination half-time was increased to 17 h in patients with impaired liver function order 20mg vytorin free shipping cholesterol and exercise, but it was not altered significantly in patients with renal impairment order vytorin 30mg fast delivery cholesterol levels malaysia. Urinary excretion of amsacrine over 72 h, typically around 12% of the dose, decreased to only 2% in patients with renal impairment and increased to 20% in patients with hepatic impairment (Hall et al. After administration of [14C]amsacrine, the total amount of radiolabel excreted in urine was 35% in patients with normal organ function, 49% in patients with liver impairment and 2–16% in patients with renal impairment. In two patients from whom biliary outflow was collected, 8% and 36% of the administered radiolabel was recovered within 72 h, < 2% being unchanged amsacrine (Hall et al. Amsacrine is taken up rapidly by nucleated blood cells in vivo, peak concentrations occurring shortly after the end of a 3-h infusion; the concentration was about five times greater than the peak plasma concentration. The kinetics of elimination from peripheral blast cells was similar to that from plasma (Linssen et al. High tissue concentrations of amsacrine were still present two weeks after treatment (Stewart et al. The concentrations in cerebrospinal fluid were < 2% of the corresponding plasma concentration in one study (Hall et al. About 97% of a dose of amsacrine is bound to protein bound in plasma in both cancer patients and healthy volunteers. Studies of human plasma in vitro showed no change in protein binding across a concentration range of 1–100 μmol/L. This typically includes biphasic elimination, with a rapid distribution phase and a more prolonged terminal elimination phase with a half-time of about 0. The pharmacokinetics was typically predictable in all species, including humans (Paxton et al. The bioavailability of orally administered amsacrine in mice (10 mg/kg bw) and rats (100 mg/kg bw) was incomplete and variable (Cysyk et al. After intravenous administration of [14C]amsacrine to mice and rats, > 50% of the radiolabel was excreted in bile within the first 2 h, and the bile:plasma ratio was > 400:1 (Cysyk et al. In mouse bile, 5′- and 6′-glutathione conjugates were present in roughly equal amounts and accounted for 70% of the excreted biliary radiolabel after administration of radio- labelled amsacrine (Robertson et al. In rats, the principal biliary metabolite was the 5′-glutathione conjugate, which accounted for 80% of the excreted radiolabel within the first 90 min and > 50% of the administered dose over 3 h (Shoemaker et al. In rat liver microsomes and human neutrophils, intermediate oxidation products have been identified as N1′-methanesulfonyl-N4′-(9-acridinyl)-3′-methoxy-2′,5′-cyclohexa- diene-1′,4′-diimine and 3′-methoxy-4′-(9-acridinylamino-2′,5′-cyclohexadien-1′-one (Shoemaker et al. The same conjugation products were reported after exposure of Chinese hamster fibroblasts to amsacrine or its methanesulfonyl oxidation product in culture. The rate of glutathione conjugate formation during exposure to the oxidation product in cultured cells was rapid, whereas formation after exposure to amsacrine was slow, suggesting a low rate of oxidation of amsacrine to its oxidation products, with subsequent conju- gation formation in this system (Robbie et al. In all of the phase I studies, the dose-limiting toxic effect was myelosuppression, resulting mainly in leuko- penia. Other effects included nausea, vomiting, fever, injection-site reaction, skin rash and discolouration (due to the yellow colour of the drug), mucositis and alopecia. Paraesthesia and hepatoxicity were seen in a few patients, but cardiac toxicity was not observed in one study (Louie & Issell, 1985). At these doses, the leukopenia is mild to moderate in most patients but more severe in around 30% of patients (Hornedo & Van Echo, 1985). Myelo- suppression is usually more severe in previously treated patients, and is much more severe with high doses of amsacrine (600–1000 mg/m2). Stomatitis and mucositis become more frequent with higher doses (> 120 mg/m2) (Slevin et al. Hepatoxicity has been reported, typically manifest as transient increases in serum bilirubin concentration and/or hepatic enzyme activity, but lethal hepatotoxicity has also been reported (Appelbaum & Shulman, 1982). Phlebitis occurred in up to 17% of patients in early studies with amsacrine (Legha et al. The more common effects were alterations in the electro- cardiogram and arrhythmia, but cardiomyopathy and congestive heart failure also occurred (Weiss et al. Amsacrine has been used safely in patients with pre- existing arrhythmia when a serum potassium concentration of > 4 mmol/L was main- tained (Arlin et al. Toxic effects on the gastrointestinal and central nervous system were observed at lethal doses in dogs (6. In subsequent studies, evidence of cardiotoxicity was not seen in rats (Kim et al. Intravenous dosing of rats at 1 or 3 mg/kg bw per day for five days resulted in hair loss, diarrhoea and leukopenia; these effects were reversible (Pegg et al. Local tissue reactions were seen when the drug was administered subcutaneously or intramuscularly to guinea-pigs or rabbits, but similar effects were seen after admin- istration of the vehicle alone, suggesting that the acidity of the vehicle (see above) may have been responsible (Henry et al. Skin rashes in personnel involved in bulk formulation of amsacrine prompted further studies in experimental animals. In the Magnussen and Kligman maximization test, amsacrine was extremely sensitizing to the skin of guinea-pigs when given as a challenge dose by direct application, while the vehicle alone produced almost no response. The animals were not sensitized for systemic anaphylaxis, however, and there was no detectable induction of antibodies in rabbits (Watson et al. There was no effect on post-spermatogonial stages and little effect on stem cells, and the sperm counts had recovered by day 56 (da Cunha et al. Eye, jaw and other skeletal malformations were observed in the fetuses at all doses. An increased frequency of resorptions and decreased fetal weight were observed at the intermediate and high doses (Ng et al. Day-10 rat embryos [strain not specified] cultured for 24 h in vitro were exposed for the first 3 h to amsacrine at concentrations of 10 nmol/L to 1 μmol/L. A dose-related increase in the frequency of malformations was observed at doses of 50–500 nmol/L, and 100% of the embryos were malformed at 500 nmol/L. The malformations consisted mainly of hypoplasia of the prosencephalon, microphthalmia and oedema of the rhombencephalon. Similar malformations were observed in the same system with etoposide (see the monograph on etoposide). Comparison of the concen- trations necessary to produce lethality and malformations in 50% of fetuses showed that amsacrine was 10 times and 20 times more potent, respectively, than etoposide (Mirkes & Zwelling, 1990). In a study reported only as an abstract, male mice were treated with a maximum tolerated dose of 15 mg/kg bw [no further details given] amsacrine and showed no signs of dominant lethal mutation. The positive effects required a dose of about 800 μg/plate, which is higher than those tested in mammalian cells. In Saccharomyces cerevisiae strain D5, amsacrine failed to induce the mitochondrial ‘petite’ mutation, but it was an effective mitotic recombinogen when testing was done under conditions permitting cell growth. The Chinese hamster cell line xrs-1 was hypersensitive to amsacrine treatment (Caldecott et al. Amsacrine caused chromosomal aberrations in cultured Chinese hamster cells, in various rodent cell lines, in HeLa cells and in cultured human peripheral blood lymphocytes. Fluorescence in-situ hybridization techniques revealed a high frequency of dicentrics and stable trans- locations in amsacrine-treated human peripheral blood lymphocytes. Additionally, amsacrine induced micronuclei and chromosomal aberrations in the bone marrow of non-tumour-bearing male and female mice. In male ddY mice, amsacrine increased the incidence of micro- nuclei in both hepatocytes and peripheral blood reticulocytes.

Betamethasone and Cinchocaine Suppositories Bill of Materials Scale (mg/suppository) Item Material Name Quantity/1000 Suppositories (g) 1 generic vytorin 20mg amex cholesterol levels 70 year old. Betamethasone and Salicylic Acid Lotion Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0 best order for vytorin cholesterol ratio score. Add 20% of item 7 in a separate vessel and add sel and slowly add item 4 with vigorous mixing; and dissolve item 2 into it. Use item 7 to rinse solve item 1 in a separate vessel and then add all vessels and add rinsings. Formulations of Semisolid Drugs 115 Betamethasone Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 70. Heat items 7 and 8 until the active ingredient is dissolved, mix with above mixture, and con- 1. Heat a mixture of items 1–5 and item 6 sepa- tinue to stir to cool to room temperature. After cooling the oleaginous phase to about 55°C, the tiacetin solution is added while mix- 1. The betamethasone dipropionate and citric acid ing to make a homogenous dispersion. Mixing are dissolved in the triacetin with mixing and should be of sufficient intensity to disperse the heat to 35°C if needed. Mixing is continued while cooling at room tem- stearate, and mineral oil are melted together by perature. Betamethasone Gel Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 1. Prepare the solution of items 1–3 at room tem- perature and solution of items 4 and 5 at about 6°C (or at >70°C). Formulations of Semisolid Drugs 117 Betamethasone Opthalmic Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 1. In a separate vessel, dissolve item 1 in 200 mL of water for injection and add to step 1 under 1. Betamethasone Valerate and Cinchocaine Ointment Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 5. Add items 1 and 2 in a small portion of the melt from step 2 in a separate vessel and homogenize 1. Homogenize for 10 minutes under homogenizer Set the mixer speed 8 rpm, manual mode, vac- to make a smooth slurry. Homogenize for 10 minutes with recirculation, phase in fat melting vessel at 65°–70°C. Each gram of foam contains hol and is dispensed from an aluminum can pressurized 1. Formulations of Semisolid Drugs 119 Betamethasone Valerate Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. Melt item 2 in a fat-melting vessel at 75°C while above and the rinsing from previous step to the mixing—do not overheat. Betamethasone Valerate Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. Add items 1, 2, and 6 to a stainless steel con- tainer and homogenize for 3 minutes. Set the mixer at temperature 40° ± 2°C, speed 10 rpm (manual mode), and mix for 20 minutes. The molten suppository mass must be kept Set the mixer at temperature 40° ± 2°C, speed stirred throughout the storage period, during 10 rpm (manual mode), vacuum 0. Homogenize at high speed while mix- dient causes skin irritation, which vanishes after ing for 3 minutes. Fill weight is 900 mg/suppository, but use a fill Carefully mix the powder with the molten mass. Bisacodyl Suppositories Bill of Materials Scale (mg/suppository) Item Material Name Quantity/1000 Suppositories (g) 10. Formulations of Semisolid Drugs 121 Biscarboxychromonyloxy Propanol Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 4. The concentrated dispersion is then added to a homogenizer heated at 80°–100°C, and the 1. The disodium salt of 1,3-bis(2-carboxychromon- remaining components of the ointment basis are 5-yloxy) propan-2-ol is added slowly in small added slowly with continuous blending. When this addition is complete, the molten oint- tion of the preheated and sterilized components ment is blended for a further 15 minutes and of the ointment base at 90°C. The ointment is then filled in presterilized eye tinued for a further 15 minutes, and then the ointment tubes, which are crimped and allowed concentrated dispersion is sterilized by heating to cool to room temperature. Breast Care Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 20. Transfer the fat phase (70°–75°C) into the man- ufacturing vessel containing aqueous phase 1. Homogenize under polyoxyl 40 stearate in the fat-melting vessel at vacuum for few minutes. Heat the purified water in the manufacturing stainless steel container at 40°–45°C and trans- vessel to a temperature of 80°–90°C. Disperse fer this dispersion to the manufacturing vessel carbopol 934 in the heated water. Homogenize from step 4 at temperature 40°–45°C; mix and the dispersion to obtain clear gel. Dissolve item 6, sodium methylparaben, sodium homogeneous cream and the stated amount of propylparaben, and sodium hydroxide in puri- budesonide per 100 g. Cool the cream to 25°–30°C while stirring con- from step 2 in the manufacturing vessel and tinuously. Budesonide Ointment Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 0. Disperse budesonide with liquid paraffin at 33°C; use homogenizer to get homogeneous suspension. Transfer the dispersion from step 2 to the oint- nated castor oil in the fat-melting vessel at ment base from step 1 in the manufacturing ves- 100°C and maintain this temperature for 20 sel while stirring. Then transfer this melted mass to the homogeneous ointment containing the stated manufacturing vessel preheated to 85°C amount of budesonide per 100 g ointment. Formulations of Semisolid Drugs 123 Burn Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 120. Mix and heat items 5–11, keeping item 7 suspended to 75°–80°C; mix the two parts while cooling; pour and fill at 40°C. Butesin Picrate and Metaphen Ointment Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 6. Adjust temperature of mass from step 5 to 50°C solution to melted lanolin and mix thoroughly. Add borax-potassium chloride solution, step 2, to oil–wax mixture with constant stirring. Formulations of Semisolid Drugs 125 Butesin Picrate Ointment Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 249.

Other beneficial effects conferred by the use of bioadhesive polymers include: • increasing the local drug concentration at the site of adhesion/absorption; • protecting the drug from dilution and possible degradation by vaginal secretions; • prolonging the contact time of the dosage form near the absorbing surface cheap 30mg vytorin cholesterol in eggs pdf. Thus such polymers have attracted considerable interest as a means of improving drug delivery at mucosal sites purchase vytorin paypal cholesterol levels diet, including the vagina. Reference has already been made to the promising results obtained using bioadhesive hyaluronane ester microspheres for vaginal drug delivery. Other bioadhesive polymers under investigation include: Polycarbophil Polycarbophil, a poly(acrylic acid) lightly cross-linked with divinyl glycol, can remain on vaginal tissue for extended periods and has demonstrated many potential clinical applications: 296 Dry vagina: the bioadhesive gel can hydrate vaginal tissue for 3–4 days after a single application. Tissue hydration is caused by an increased blood flow, thus increasing transudation of vaginal fluid though the intercellular channels of the vaginal epithelium. Clinical assessment of local tissue pH in postmenopausal women shows a reduction in pH from about 7 to 4 and maintenance of this acidic pH for about 3–4 days. This acidic pH is an unfavorable environment for pathogens, thereby protecting against bacterial vaginosis. Spermicide-antiviral: the polymer appears to be an effective delivery system for the spermicidal/antiviral agent nonoxynol-9. By its ability to adhere to vaginal tissue while retaining nonoxynol-9 in its gel structure, it is an excellent extended effect spermicide. In contrast, the bioadhesive gel containing nonoxynol-9 attaches to lymphocytes and maintains sufficient contact time to allow the nonoxynol-9 surfactant to disrupt the cell wall, thus eliminating the lymphocyte and killing the virus within. Progesterone delivery: as described above, estrogen replacement therapy increases the risk of endometrial cancer when used alone. This risk can be eliminated by treatment with a progestational agent for up to 14 days a month. The vaginal delivery of a polycarbophil gel loaded with progesterone has been shown to allow the extended vaginal delivery of the drug for 2–3 days from a single dose and protect the endometrium against cancer. Low serum levels of progesterone were detected after vaginal delivery, which corresponds to fewer side-effects. A commercial progesterone-loaded polycarbophil gel preparation for intravaginal delivery, Crinone, has recently been launched. Smart hydrogel Smart hydrogel preparations, comprising poly(acrylic acid) and a poloxamer (see Section 16. The temperature- dependent gelling of the system helps to prevent leak-back and provides sustained release properties. Smart hydrogel preparations containing estradiol have shown similar bioavailability to a commercial vaginal cream and suppository, even though the gel contained only 20% of the relative estradiol dose. However, the low and erratic bioavailability of biopharmaceuticals via this route necessitates the use of absorption enhancers. Until safe, non-toxic absorption enhancers can be found, the route is of limited potential. A further major limitation of this route is the lack of reproducibility resulting from cyclic changes in the reproductive system. Finally, no matter what degree of optimization can be achieved via this route, it can only ever benefit approximately 50% of the population! Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Give examples of the classes of the pharmaceutical agents which are presently marketed as topical formulations for vaginal administration. Which other epithelial membrane has a structure most similar to that of the vaginal epithelium? During which phase of the menstrual cycle is the vaginal epithelia thickest and the epithelial tight junctions most cohesive, thereby reducing the absorption of hydrophilic compounds via the paracellular route? Which of the following do not leak through the intercellular channels of vaginal epithelium at the late luteal phase and early follicular phase? What factor controls the pH in the vaginal lumen at between pH 4 and pH 5, preventing the proliferation of pathogenic bacteria? Describe the types of absorption enhancers under development for use in vaginal route. Describe the possible reasons for enhanced vaginal vaccination using microparticulate systems. Research has recently been directed towards the development of alternatives to the parenteral route, such as the transdermal, nasal and other routes thus far discussed in this book, for the systemic delivery of such drugs. However, unlike the other routes described in this text, ophthalmic drug delivery is used only for the treatment of local conditions of the eye and cannot be used as a portal of drug entry to the systemic circulation. Nevertheless, this route warrants study within the general context of drug delivery and 299 targeting, as the local delivery of drugs to their site of action represents a form of drug targeting, reducing the dose needed to produce a pharmacological effect and also minimizing side-effects. Furthermore, significant advances have been made to optimize the localized delivery of medication to the eye, so that the route is now associated with highly sophisticated drug delivery technologies; some of these technologies are unique to the eye and many are also found in the other delivery routes. The eye is a sensory organ, prone to a wide variety of diseases which may be of a systemic origin, such as diabetes or hypertension, or peculiar to the eye, such as glaucoma, cataract and macular degeneration. Furthermore, since the eye is located on the surface of the body, it is also easily injured and infected. According to the location of diseases, ocular disorders are grouped as periocular and intraocular conditions. Periocular diseases include: Blepharitis An infection of the lid structures (usually by Staphylococcus aureus) with concomitant seborrhea, rosacea, a dry eye and abnormalities of the meibomein glands and their lipid secretions. Conjunctivitis The condition when redness of the eye and the presence of a foreignbody sensation are evident. There are many causes of conjunctivitis, but the great majority are the result of acute infection or allergy. Keratitis The condition in which patients have a decreased vision, ocular pain, red eye, and often a cloudy/opaque cornea. Trachoma This is caused by the organism Chalmydia trachomatis; it is the most common cause of blindness in North Africa and the Middle East. Dry eye If for any reason the composition of tears is changed, or an inadequate volume of tears is produced, the symptom of dry eye will result. Dry eye conditions are not just a cause for ocular discomfort, but can also result in corneal damage. Periocular diseases such as these are relatively easily treated using topical formulations. Intraocular conditions are more difficult to manage and include intraocular infections: i. Such infections carry a high risk for damage to the eye and also afford the possibility of spread of infection from the eye into the brain. A common intraocular disease is glaucoma, considered to be one of the major ophthalmic clinical problems in the world. Recently, physicians have become more familiar with the condition known as normotensive glaucoma.