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Patient 9930010 (ciprofloxacin group) with a history of Arnold-Chiari allegra 180 mg amex allergy testing on cats, insertion of a ventriculo-peritoneal shunt cheap 180mg allegra with visa allergy symptoms numbness, and recurrent seizures (not on baseline anticonvulsant) had a seizure on Day +1 cheap allegra 180mg line allergy treatment coughing. By June 30 buy discount allegra 180 mg on line allergy forecast greenwich ct, 2003, 404 ciprofloxacin patients and 315 control patients would have been eligible for 1-year post-treatment follow-up. Other commonly used monotherapies in the control group included Augmentin® (7%; 34/507), Zithromax® (6%; 30/507), Keflex® (6%;28/507) and Omnicef® (6%; 29/507). Clinical Reviewer’s Comment: Table 4 was expanded by the reviewer to include more variables than the applicant’s original table. The race distribution and percentage of patients born prematurely were very similar in the two groups. The distribution of infections, which led to enrollment in the trial, was very different in the two groups. The age groups and distributions of patients in each age group that were studied are shown in Table 5. Of the patients ≤ 5 years of age, 48% (235/487) were in the ciprofloxacin group and 52% (265/507) were in the control group. More ciprofloxacin patients (12%; 58/487) were 12 years to <17 years of age compared to control patients (4%; 19/507). Among ciprofloxacin-treated patients, 17% (81/487) had used a previous antimicrobial, while among control patients, less than 1% (3/507) had used a previous antimicrobial. Ciprofloxacin and Bactrim® were the most commonly used previous antimicrobials in the ciprofloxacin group. Clinical Reviewer’s Comment: Ofloxacin was used previously in 9/487 (2%) of ciprofloxacin patients and none of the control patients. The overall rate of any medical history for patients treated with ciprofloxacin was 84% and 83% in the control group. There were many individual conditions for which the percentages differed greatly between groups. Table 6 shows all classes of conditions for which the difference between groups was at least 2%. The medical history results were consistent with the infections causing patients to be entered into the trial. Many more ciprofloxacin patients had histories in the genitourinary system, and many more control patients had histories in the respiratory infections. The ciprofloxacin group also had many more patients with histories of various types of operations. Antimicrobial use was much more common among ciprofloxacin patients (41%; 201/487) than control patients (17%; 88/507). Ciprofloxacin patients also had higher use of vitamins (8% [40/487] versus 2% [11/507]), antacids (6% [27/487] versus 2% [11/507]), antifungals for dermatologic use (4% [20/487] versus 1% [7/507]), urologicals (5% [24/487] versus 0% [0/507]), antimycotics for systemic use (3% [13/487] versus <1% [1/507]), analgesics (23% [112/487] versus 14% [72/507]), and anti-asthmatics (14% [70/487] versus 11% [55/507]). There was a difference between groups in the number of patients using general anti-infectives for systemic use (31% [152/487] for ciprofloxacin-treated patients, 17% [84/507] for control patients). The ciprofloxacin group also had higher incidence rates of treatment-emergent use of alimentary tract and metabolism medications (9% [45/487] versus 4% [19/507]), nervous system medications (19% [93/487] versus 14% [71/507]), and sensory organ medications (10% [40/487] versus 7% [34/507]). The control group had a higher incidence rate of treatment-emergent use of respiratory system medications (23% [111/487] versus 34% 170/507]). When limited to antimicrobials being used at the same time as study drug therapy, there were more ciprofloxacin patients using concomitant antimicrobials than control patients (16% [77/487] versus 3% [13/507]). The mean duration of treatment was one day longer for the ciprofloxacin patients than for the control patients (12. Ciprofloxacin-treated patients had higher mean durations of both oral therapy (12. The maximum duration of ciprofloxacin treatment was 88 days, while the maximum duration of control therapy was 70 days. The applicant acknowledges the limitations in interpreting the data based up the same reasons identified by the reviewer. The study was not blinded or randomized and enrollment into the comparator arm was not temporal to the ciprofloxacin arm (i. The distribution of infections, which led to enrollment in the trial, was very different in the two groups. In the control group, 70% of patients were enrolled due to otitis media orpharyngitis/tonsillitis, while only 37% of ciprofloxacin patients were enrolled due to these infections. The most notable difference was in the patient age group of 12 years to < 17 years (12%; (58/487) of ciprofloxacin patients compared to 4% (12/507) control patients. There was a large difference between groups in the use of previous antimicrobials. Among ciprofloxacin-treated patients, 17% (81/487) had used a previous antimicrobial, while among control patients, only 1% (3/507) had used a previous antimicrobial. Ciprofloxacin and Bactrim® were the most commonly used previous antimicrobials in the ciprofloxacin group. The control group had a higher incidence of medical histories of conditions in the nervous system and sense organs (53% [270/507] control versus 31% [150/487] ciprofloxacin; mainly attributed to a higher incidence of otitis media), respiratory system (62% [315/507] control versus 37% [181/487] ciprofloxacin; mainly attributed to differences in upper respiratory infections, pharyngitis, and chronic sinusitis), and injury and poisoning (40%[205/507] control versus 17% [85/487] ciprofloxacin; mainly attributed to allergy). Differences in baseline abnormalities or medical histories of musculoskeletal adverse events. Known underlying rheumatological disease, joint problems secondary to trauma or pre-existing conditions known to be associated with arthropathy were to be excluded from the study. However, 7% (32/487) of ciprofloxacin patients and 5% (24/507) control patients were enrolled with a medical history of any abnormal musculoskeletal or connective tissue finding. Prevalence rates of concomitant medication use (at the time of enrollment) were 76% (9369/487) for ciprofloxacin patients and 68% (347/507) for control patients (data not shown). Antimicrobial use was much more common among ciprofloxacin patients (41%) than control patients (17%). Ciprofloxacin patients also had higher use of vitamins (8% [40/487] versus 2% [11/507]), antacids (6% [27/487] versus 2% [11/507]), antifungals for dermatologic use (4% [20/487] versus 1% [7/507]), urologicals (5% [24/487] versus 0% [0/507]), antimycotics for systemic use (3% [13/487] versus <1% [1/507]), analgesics (23% [112/487] versus 14% [72/507]), and anti-asthmatics (14% [70/487] versus 11% [55/507]). The differences between treatment groups outlined above should be considered when reviewing adverse event rates for the two treatment groups and the population of ciprofloxacin patients should not be directly compared to the population of control patients. The 13 patients who were premature discontinuations in the ciprofloxacin group had: • Arthralgia – shoulder pain (mild); jaw pain (moderate); and R wrist pain [one patient each] • Dizziness – (one moderate one mild) [2 patients] • Headache (mild) • Tachycardia (moderate) • Rash (mild) • Injection site reaction (mild) • Allergic reaction (mild) • Vomiting (mild) [2 patients] • Otitis media, worsening (severe) • Bacteremia (moderate) • Sinusitis (one moderate one mild) [2 patients] • Infected abdominal wounds (one moderate, one severe) [2 patients] • Urticaria, hives (severe) All ciprofloxacin patients had resolution of their events. The 3 patients who were premature discontinuations in the comparator group had: vomiting (mild) and rash (moderate) in one patient each who received amoxicillin; and abdominal pain (mild) in a patient who received cefzil. Two patients experienced serious musculoskeletal events; one patient reported osteomyelitis, and one reported arthralgia. The five events, which all occurred in different patients were: vertigo, acute asthma (2 patients), peritonisllar abcess, and increasing pleural effusion (pt. The patients with asthma and the peritonsillar abcess received remedial drug therapy. There were 2 patients with pseudomembranous enterocolitis (270024 and 500011); one of these patients also had gastroenteritis (270024). Of these, 7/35 ciprofloxacin patients and none (0/9) of the comparator patients had an event(s) occurring by Day +42 as well as an event(s) occurring between Day +42 and one year.
Obviously purchase generic allegra online allergy testing for mold, the small percentage of the population who are poor metabolizers may be at considerable risk of adverse effects from the usual doses of many drugs order discount allegra allergy list. Age Few pharmacokinetic studies are carried out beyond the range of 28–40 years and discount 120 mg allegra mastercard allergy forecast duluth mn, consequently cheap allegra express allergy shots testimonials, there are few data on oral bioavailability for extremes of age. Gastric fluid is less acidic in newborns than in adults, which can affect the absorption of ionizable and acid-labile drugs. Decreased enzymatic activity, including hepatic first-pass metabolism, is associated with the elderly, which may result in an increased oral bioavailabiliy for drugs subject to the first- pass effect. The effect of the shunt is to increase the presistence of the drug in the body and, provided the concentrations of the drug at its sites of action are sufficiently high, to prolong its duration of action. It is important to remember that although a drug molecule may be predominantly absorbed via one particular route/mechanism, it is also likely that suboptimal transport will occur via alternative routes and mechanisms. Diffusion is driven by a concentration gradient and is inversely related to molecular weight. The junctional complexes begin immediately below the luminal surface and are made up of three components (Section 1. Thus only small hydrophilic molecules, such as, for example, mannitol, are capable of squeezing through the junctional complexes to be absorbed via the paracellular route. The rate of absorption is governed by Fick’s Law and is determined by the physicochemical properties of the drug as well as the concentration gradient across the cells (Section 1. Carrier-mediated transport Amino acid transporters, oligopeptide transporters, glucose transporters, lactic acid transporters, monocarboxylic acid transporters, phosphate transporters, bile acid transporters and other transporters present on the apical membrane of the epithelial cells serve as carriers to facilitate nutrient absorption by the intestine. Drug moieties possessing similar structures to nutrients that are absorbed by such carriers may also be absorbed in this manner. Endocytic processes Considerable evidence has accumulated indicating that macromolecules and microparticulates can be taken up by the intestinal enterocytes, generally via pinocytosis. For example, studies have shown that receptor-mediated endocytosis via enterocytes is a major pathway for the intemalization of certain antisense oligonucleotides. In contrast, endocytic uptake of macromolecules and microparticles is carried out extensively by the M cells of the 144 Peyer’s patches. Transcellular shuttling through the M cells to the underlying Peyer’s patch may involve an adsorptive and/or receptor-mediated process, with membrane-bound vacuoles or vacuoles already present in the apical cytoplasm of the cells (see below, Section 6. Therefore, they are ionized to a certain extent, determined by their pKa and the pH of the biological fluid in which they are dissolved; the extent of ionization can be quantified by the Henderson-Hasselbalch Equation (see Section 1. According to the pH-partition hypothesis, the nonionized form of a drug, with a more favorable oil/water partition coefficient (Ko/w) than the ionized form, is preferentially absorbed. For example, the absorption of salicylic acid, a weakly acidic drug, is approximately twice as high at pH 4 than at pH 7. By contrast, quinine, a weakly basic drug, is absorbed approximately four times higher at pH 7 than at pH 4 (Table 6. The numbers refer to 1, atenolol; 2, practolol; 3, pindolol; 4, metoprolol; 5, oxprenolol; and 6, alprenolol. Generally, the larger the partition coefficient, the more lipophilic is a compound, and the more readily would it partition into biological membranes. By contrast, hydrophilic atenolol, with the smallest partition coefficient, shows the lowest permeability. Some drugs exhibit a lower absorption than expected on the basis of their partition coefficient. This reduced absorption is thought, in some cases, to be due to the P-glycoprotein efflux effect (see above, Section 6. The results shown with the squares represent the relationship between intestinal absorption clearance (ka) observed from the in situ jejunum loop in the presence (■) and absence (□) of cyclosporin A in rats and octanol-buffer (pH 7. The numbers refer to 1, atenolol; 2, nadolol; 3, acetamide; 4, celiprolol; 5, acebutolol; 6, doxorubicin; 7, timolol; 8, sulfathiazole; 9, quinidine; 10, sulfamethoxazole; 11, digoxin; 12, cyclosporin A; 13, vinblastine; 14, b-estradiol; 15, verapamil. The ionized form of a drug displays a higher dissolution rate and greater solubility than the nonionized form (see Section 1. Drug solubility is also a function of the crystalline, hydrate and salt form (see Section 1. For example, the amorphous form of a drug moiety is usually more soluble than the corresponding crystalline form (e. The solubility of a salt form of a lipophilic drug is higher than the free form and conversion of the free base to the corresponding salt represents a common method of increasing drug solubility. Symposium on Drug Absorption, Metabolism and Excretion, Scientific section of the American Pharmaceutical Asso. The Noyes-Whitney equation describes the influence of surface area (S) and other factors on the dissolution rate: (Equation 6. A reduction in particle size results in an increase in the surface area, which facilitates an increase in the dissolution rate and therefore, also, an increase in the rate of absorption. Drugs administered as suspension are generally rapidly absorbed because of the large available surface area of the dispersed solid. For solid dosage forms such as tablets and capsules, decreasing the particle size facilitates dissolution and thus absorption. Peak blood levels occurred much faster with the smaller 148 particles (50 µm) than with large ones (800 µm), confirming that particle size must be considered in order to optimize absorption. For this reason, many poorly soluble, slowly dissolving drugs for oral drug delivery are marketed in a micronized or microcyrstalline form. These include: Wetting agents Wetting agents are surfactants that lower the interfacial tension and contact angle between solid particles and liquid vehicles. These agents are therefore commonly used to improve the wettability of hydrophobic compounds. Polysorbate 80 is the most widely used wetting agent because of its low toxicity and high compatibility with most formulation ingredients. For example, the common pharmaceutical wetting agent, sodium dodecyl sulfate, has been shown to increase the absorption of drugs and peptides across the human intestinal epithelium. Studies have confirmed that such agents enhance absorption via the paracellular pathway. Diluents Diluents are inert substances added to the active ingredient to bulk up the formulation, in order to make a reasonably sized tablet, or to fill a capsule. Carbohydrates are commonly used, such as lactose, dextrose, sucrose, and microcrystalline cellulose. Hydrophilic diluents promote rapid tablet disintegration and therefore liberate the drug quickly from the dosage form, which promotes absorption. Some diluents dissolve very slowly and therefore release of the drug occurs by tablet erosion, rather than tablet disintegration. However, a hydrophobic diluent impedes penetration of gastrointestinal fluids, so that dissolution of drug occurs only from the surface of the plug-shaped mass. Binders (adhesives) In tableting, binders are used to bind powders together in the wet granulation process.
Another method of deposition 120mg allegra free shipping allergy testing fargo nd, that of interception discount generic allegra uk allergy or sinus, is of importance for fibers but is not of importance for drug delivery purchase 180mg allegra visa allergy symptoms zoloft. As a consequence of these physical forces acting on the aerosol particle order 120mg allegra free shipping allergy forecast wisconsin, its deposition in the lung is highly dependent on diameter. Generally: • Particles larger than 10 μm will impact in the upper airways and are rapidly removed by coughing, swallowing and mucociliary processes. An 8 μm particle inhaled at 30 L min−1 has approximately a 50% chance of impacting on the throat. If the particles are less than about 3 μm then appreciable deposition in the A region is likely to occur. The “respirable fraction” of a therapeutic aerosol is often quoted as the percentage of drug present in aerosol particles less than 5 μm in size. Each bifurcation results in an increased probability for impaction and the decrease in airway diameter is associated with a smaller displacement required for a particle to contact a surface. Thus to travel down the airways, the drug particles must pass through a successive series of branching tubes of constantly decreasing size. The aerosol particles must constantly change direction in order to remain airborne. Thus lobes of the lung which have the shortest average pathlength will show greatest peripheral deposition. For maximum effect, breath-holding for a period of 5–10 seconds post-inspiration is recommended. Under idealized conditions a 5 μm particle will settle a few mm during a 5-second breath hold. The bronchoconstriction of asthma has a greater influence on exhalation than inhalation and thus deposition by sedimentation may be greater than normal. Therefore a number of terms are used to adequately characterize an aerosol sample: • Particle size is conventionally defined as the aerodynamic diameter, which is the diameter of a spherical particle with unit density that settles at the same rate as the particle in question. Environmental fibers 50 μm in length can reach the A region because they align with the inspired airflow. Such materials then impact in the airways by a process of interception with the airway walls. Most micronized drugs for inhalation will have particle densities around 1, although materials produced by freeze-drying or spray-drying methods are likely to be significantly less dense. It should not be assumed, however, that the uptake of water vapor will always occur. If the drug is given as an aerosolized powder then the drug first needs to dissolve in the mucus layer. Although mucus has a very high water content, varying between approximately 90–95%, its viscosity may result in a slow dissolution of drugs. Thus dissolution may be a rate determining step, especially for poorly soluble drugs, such as some of the corticosteroids which are delivered as dry powder aerosols. Improvement of drug penetration into mucus has been attempted using mucolytic drugs such as N- acetylcysteine, which act to reduce mucus viscosity. Highly water-soluble drugs, given as dry powder 256 aerosols, may dissolve at the very high relative humidity (>99%) present in the airways air and impact as solution droplets. Once in solution, the drug will diffuse through the mucus layer and enter the aqueous environment of the epithelial lining fluid. The rate of diffusion through the mucus will be dependent upon such factors as: • the thickness of the mucus layer; • mucus viscosity—although it should be appreciated that it is the viscosity of the mucus gel intersticies (i. Mucus secretion may be stimulated as a response to “assault” by what the lung perceives as foreign bodies such as microorganisms and dusts or irritants such as cigarette smoke. Airways disease states such as bronchitis, cystic fibrosis and asthma are often associated with a hypersecretion of mucus. Clearly this presents a far greater barrier than is seen in the normal healthy lung. Many studies have been performed with a variety of antibiotics delivered by aerosol for the treatment of chronic lung infections. The studies have produced mixed results with delivery to the lung from the bloodstream (after oral or parenteral dosing) often producing better clinical response. A number of factors, including the efficiency of drug delivery, may be responsible for these observations, but the overproduction of mucus in these disease states also seems likely to play a major role in preventing the drug reaching its target microorganism. A detailed discussion of the structure and properties of mucus and respiratory mucins is given in Chapter 9 (Section 9. The cilia beat at approximately 1,000 beats min−1 in an organized fashion and the ciliary movement may be conceived as a form of rhythmic waving which enables hook-like structures at the ciliary tips to propel mucus along the airways to the throat (see Section 9. Mucociliary clearance is an organized, complex process which is highly dependent upon the composition and depth of the epithelial lining fluid and the viscoelastic properties of the mucus. This may cause an overloading of the ciliary transport process, resulting in 257 a debilitated mucociliary clearance and the build-up of mucus as a thick, highly viscous layer. Thus while the mucociliary clearance of particles takes hours under normal circumstances, induced coughing may result in rapid removal of mucus and any associated drug within minutes. It should be remembered, however, that aerosolized drug deposition is likely to occur over a large surface area in the healthy and mild to moderate airways diseased lung. Coughing will remove mucus from a few localized areas where build-up has occurred and thus the fraction of the deposited dose removed by coughing is likely to be small. In cases of severe lung disease, drug deposition is likely to be highly localized and the situation may be different. For example, in cystic fibrosis patients, high levels of gentamicin, representing significant proportions of the deposited dose, were found in the sputum, when the aerosolized drug was deposited in the central airways. The main route is via the mucociliary escalator, although transport from the A region to the start of the mucociliary escalator is a very slow process and may involve transport through interstitium and lymphatic tissues in addition to a transfer by random movement by macrophages. Macrophages may also be transported via lymphatic systems to lymph nodes and the bloodstream. The uptake of particles by macrophages is a fairly rapid process but the subsequent clearance of particle-laden macrophages only occurs over days or weeks. Absorption is clearly important for systemically-acting drugs since it is one element of the events leading to delivery of drug to its site of action. Absorption is equally important for locally-acting drugs since for these compounds it represents removal of drug from its site of action. Metabolism of drugs is also an important consideration since it may lead to drug inactivation or the production of active or toxic metabolites. These same features also offer great potential for the delivery of systemically-acting compounds. The surface area of the airways is approximately 140 m, slightly larger than that of the small intestine.
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