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Telepharmacy is a rapidly growing area of communication within pharmaceutical care delivery, especially in rural areas. The purpose of this literature review is to determine how telepharmacy is currently being practiced within community and ambulatory pharmacy settings, its effectiveness, and how it is being regulated across the United States. A literature review was performed using PubMed, Ovid MEDLINE, and the Google search engine. State-specific rules were researched using board of pharmacy and legislative online resources. Telepharmacy has been successfully implemented within community pharmacy settings through the creation of remote dispensing sites. The increasing focus of state regulations on telepharmacy services and practices shows the growth and acceptance of this modality of pharmacy practice. There is wide variation among state regulations pertaining to the setup and operation of telepharmacies. Trends in telemedicine show that telepharmaceutical care is likely to continue to expand as it allows for a better allocation of resources and access to more patients. However, research needs to be conducted to specifically analyze the value and place for telepharmacy services.

Objective. To determine how the standards for teaching pharmacy history were met by U.S. pharmacy schools, whether schools wanted to expand their commitment to pharmacy history, what pedagogical assistance, if any, was desired, and whether elective courses were offered. Methods. There were 133 school deans who were asked to identify the responsible faculty for teaching pharmacy history. A 10-question online survey instrument was designed and emailed to these faculty or the dean if no faculty were identified. Follow-up emails were sent at 2-week intervals. If they were non-responsive after three attempts, then telephone solicitation was attempted. Results. There were 100 schools (75%) that responded. Fifty-three percent were public and 47% were private; with 50% having class sizes of 100 or less, 41% with 101-250, and 9% having over 250. Eighty-six percent of respondents meet the ACPE requirement within a required course. Seventy-two percent devote only one to five hours of instruction to meet the requirement. Sixty-eight percent use no supporting literature, and among those who do, there was no common textbook. Interestingly, 21% wanted more teaching time, and 91% desired pedagogical assistance, varying from a packaged course (26%) to a syllabus with assignments and assessment banks (23%). Conclusion. Since no time or material guidelines were established to fulfill the ACPE pharmacy history educational requirements, these results provide a starting point to judge what is adequate and/or preferred. With the development of teaching guidelines and adoptable teaching materials, the pedagogical solution to this ACPE standard may become more complete and consistent.

The first dual-degree program combining both the doctor of pharmacy (PharmD) and the doctor of medicine (MD) degrees was designed and launched by Rutgers, The State University of New Jersey, in academic year 2013-2014. This joint effort was led by the Ernest Mario School of Pharmacy (EMSOP) and the Robert Wood Johnson Medical School (RWJMS) to combine expertise in both diagnostic and treatment facets of health care and to prepare graduates for leadership roles in providing and managing comprehensive patient care in a variety of settings. One area of potential value of these skill sets is the drug development industry. A survey was conducted among pharmaceutical executive stakeholders associated with a postdoctoral training program to assess the perceived value of this new dual-degree skill set and to identify particular functions where the combined training has its best fit. Results indicate that the combined nature of this training is highly valued in this setting, especially in the areas of clinical pharmacology, drug safety and pharmacovigilance, medical affairs/strategy, and medical science liaisons. Future monitoring of graduates will further define the value of this dual degree in this and other health care settings.

To the Editor: We thank Dr. Tekiner for his insightful and positive comments in response to our manuscript.[1][1] Dr. Tekiner observes that the teaching of the history of pharmacy has been neglected in many countries. This has also been the case in the United States, and the findings of our study

The objectives of the study were: (a) to determine pharmacists' perceptions of the importance of Healthy People (HP) 2000 objectives for their patients and community; and (b) to analyze pharmacists' perceived perceptions about recent trends in the characteristics of patients. Three hundred one useful questionnaire were collected from pharmacists who either own or manage a pharmacy located in New Jersey's 67 cities eligible for financial assistance. Pharmacists consider health objectives which are directly linked to health care such as preventing, detecting, and controlling hypertension, heart disease, stroke, cancer, diabetes, and disabling conditions, to be very important. Pharmacists agree to some extent that their patients are now more willing to accept pharmacy counseling services with their prescriptions than before. In conclusion, pharmacists considered objectives related to preventive services to be the most important for HP 2000 objectives, and health promotion and health protection to be less important. The findings of this study will enhance the understanding of pharmacists' perceptions of community health issues and will be beneficial to attain the objectives of HP 2010.

I believe that the professional education of pharmacists benefits substantially from the inclusion of the history of pharmacy as a formal part of the professional curriculum. Incorporating a few lectures that attempt to summarize the history of pharmacy within the framework of another professional practice course is better than nothing. However, my observations convince me that a specific course in the history of pharmacy, offered as a professional elective, is much more effective in developing a conscious appreciation of the importance and value of the history of pharmacy. Ideally, specialists and scholars in the history of pharmacy should take the lead in providing this instruction. Realistically, however, it is unlikely that most of our colleges are ready to commit a faculty position for this purpose. Who then will serve as teachers of the history of pharmacy? In many cases, a pharmacist-faculty member who has a serious interest in the history of pharmacy may be able to serve as an effective instructor for an introductory history of pharmacy course. My predecessor, the late Dean Roy A. Bowers, and I are examples of such teachers of the history of pharmacy. Dean Bowers developed his interest in the history of pharmacy by his contact with Dean Kremers and Professor Urdang when he was an undergraduate and graduate student at the University of Wisconsin in the 1920s and 1930s. He was later influenced by his association and collaboration with another distinguished scholar in the history of pharmacy, Professor David L. Cowen, of Rutgers University. When Dean Bowers came to Rutgers in 1951, Professor Cowen taught a required course in the history of phar

Background and Objectives Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use. Methods A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state. Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method. Results A total of 28 subjects completed the study. Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%. Conclusion The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study. Clinical Pharmacology & Therapeutics (1999) 65, 389–394; doi

The objectives of the study were: (a) to determine pharmacists' perceptions of the importance of Healthy People (HP) 2000 objectives for their patients and community; and (b) to analyze pharmacists' perceived perceptions about recent trends in the characteristics of patients. Three hundred one useful questionnaire were collected from pharmacists who either own or manage a pharmacy located in New Jersey's 67 cities eligible for financial assistance. Pharmacists consider health objectives which are directly linked to health care such as preventing, detecting, and controlling hypertension, heart disease, stroke, cancer, diabetes, and disabling conditions, to be very important. Pharmacists agree to some extent that their patients are now more willing to accept pharmacy counseling services with their prescriptions than before. In conclusion, pharmacists considered objectives related to preventive services to be the most important for HP 2000 objectives, and health promotion and health protection to be less important. The findings of this study will enhance the understanding of pharmacists' perceptions of community health issues and will be beneficial to attain the objectives of HP 2010.

The bioavailabilities and bioequivalences of single 200-mg doses of itraconazole solution and two capsule formulations were evaluated in a crossover study of 30 male volunteers. The two capsule formulations were bioequivalent. The bioavailabilities of the solutions itraconazole and hydroxyitraconazole were 30 to 33% and 35 to 37% greater, respectively, than those of either capsule. However, the maximum concentrations of the drug in plasma ( C max ), the times to C max , and the terminal half-lives were comparable for all three formulations. These data indicate that the bioavailabilities of itraconazole and hydroxyitraconazole are enhanced when administered as an oral solution instead of capsules.

To evaluate the effect of food on the bioavailability of itraconazole (ITR) hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solution under multiple-dose to steady-state conditions, and to determine the pharmacokinetics of ITR solution at steady state.Open-label, randomized, multiple-dose, crossover studyUniversity-affiliated health center.Thirty healthy men randomized to one of two treatment sequences (fasted-fed, fed-fasted).Subjects were either fasted or fed a standard breakfast before receiving ITR oral solution 200 mg once/day for 15 days. Crossover phases were separated by a 4-week washout period.On day 1, blood samples were collected before the dose (time zero) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after the dose. Trough samples were obtained before the dose on days 4, 7, 12, 13, and 14. On day 15, samples were obtained at the same times as day 1, and at 36, 48, 72, 96, 168, 240, and 360 hours. Samples were analyzed by high-performance liquid chromatography for ITR and its major metabolite hydroxyitraconazole (OH-ITR). Urine was collected on days 1 and 15 before and 0-8 and 8-24 hours after the dose; HP-beta-CD was measured by size-exclusion chromatography. Mean bioavailabilities of ITR and OH-ITR were 43% and 38% higher, respectively, when ITR solution was taken as a single dose under fasted conditions. With multiple dosing, steady state was achieved by day 14. At steady state, mean bioavailabilities were 29% and 17% higher, respectively, in the fasted state; terminal half-life was similar under fasted and fed conditions (mean 39.8 and 37.5 hrs for ITR, respectively; 27.3 and 26.2 hrs for OH-ITR, respectively). HP-beta-CD was eliminated almost exclusively in urine.The bioavailability of ITR and OH-ITR is enhanced when ITR oral solution is given in the fasted state; this was true for both single and multiple dosing to steady state.

To the Editor. The statement by Brown and the follow-up statement by Knapp and Schommer in a recent issue of the Journal are informative and thought-provoking for the academy, as well as for the profession of pharmacy as a whole.1,2 Brown opines that the growth in the number of pharmacy graduates since the beginning of the 21st century will result in “looming joblessness” for pharmacy graduates. Knapp and Schommer acknowledge that “pharmacy education expansion is a key issue,” and that the academy “likely overshot the ideal balance” between demand and supply with reference to pharmacy graduates since the start of the 21st century. With these concerns in mind, it is enlightening to consider the growth in medical school enrollments over a comparable period of time as reported in a recent article in the New England Journal of Medicine.3 Data summarized in the New England Journal of Medicine report that the 10-year growth rate in first-year enrollments in US medical schools (both allopathic and osteopathic) between 2002 and 2012 was 30%. The projected 15-year first-year enrollment growth rate between 2002 and 2017 is 44%. These percentages can be viewed as reasonably consistent with the recommendation in 2006 by the Association of American Medical Colleges for a 30% increase in medical school enrollments over a 10-year period.3 Data reported by Brown are in terms of the number of pharmacy graduates rather than first-year enrollments.1 However, since the attrition rates in US medical schools are historically below 10%, first-year medical school enrollment data can serve as a reasonable surrogate for number of graduates.4 Data reported in Brown’s article indicate that the 10-year growth rate in the number of US pharmacy graduates between 2001 and 2011 was 71%. The projected 15-year growth rate between 2001 and 2016 is 105%. These comparisons make it clear that the growth rates in enrollments and graduation numbers in US pharmacy colleges and schools during the first 2 decades of the 21st century have been more than double the comparable rates of growth in US medical schools. This seems to provide further credence to the points made by Brown, and by Knapp and Schommer in their articles.

OBJECTIVE:To summarize the pharmacology, pharmacokinetics, efficacy, and safety of cisapride, and to evaluate its potential therapeutic role.DATA SOURCES:A computerized search of the MEDLINE database was used to identify English-language publications of cisapride data in humans. The MEDLINE search was supplemented by review article bibliographies. There was no attempt to limit the search to a specific gastrointestinal motility disorder.STUDY SELECTION:The MEDLINE search alone identified 165 citations. Because of the volume of available human cisapride data, the focus of the efficacy section is on complete published reports of controlled clinical studies. Abstracts and uncontrolled data are discussed only when other information is unavailable to address important aspects.DATA EXTRACTION:Information regarding study design, study population, results, and safety was recorded from each publication. The placebo response to gastrointestinal complaints in patients with motility disorders is high. Therefore, objective evidence of improvement was emphasized when documentation was available.DATA SYNTHESIS:Cisapride stimulates the motility of smooth muscle lining the esophagus, stomach, small intestine, and colon, and increases the tone of gut sphincters in vitro and in vivo. In controlled investigations, cisapride was superior to placebo in relieving symptoms associated with reflux esophagitis, nonulcer dyspepsia, and gastroparesis. Similar symptom and healing effects were observed with cisapride and histamine (H)2-antagonists in reflux esophagitis. Cisapride was either equal to or superior to metoclopramidein relieving reflux symptoms. However, metoclopramide was associated with significantly more central nervous system adverse effects. Cisapride was well tolerated, with adverse effects limited primarily to the gastrointestinal tract.CONCLUSIONS:Cisapride represents an attractive alternative to metoclopramidefor the treatment of a variety of motility disorders. Because it addresses a primary underlying cause of reflux esophagitis, cisapride may also prove to be an effective alternative to acid suppressants in the management of this disorder.

The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59% that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.

The current furor surrounding the generic drug approval process adds to the continuing debate over generic drug products

The effect of altered urinary pH on the renal excretion of doxycycline, with both single- and multiple-dose regimens, was studied in humans. Alkalinization of the urine resulted in higher cumulative amounts of doxycycline excreted during both single and multiple-dose regimens. The increased excretion was reflected in larger renal clearances and shorter half-lives for both regimens when the alkaline condition was compared to the control condition. Half-life values increased from the single- to the multiple-dose regimen under both alkaline and control conditions. However, the increase in half-life values from single- to multiple-dose administration under the alkaline condition was shorter than the half-life change under control conditions.

Ritanserin is an investigational serotonin-S2 receptor antagonist with activity in a variety of psychiatric disturbances characterized by dysthymia or anxiety. This investigation evaluates acute safety and tolerability of ritanserin in 12 healthy males. Ritanserin 10 mg, 20 mg, and placebo were administered as single doses in a randomized, double-blind, crossover fashion. Treatment effects on vital signs, laboratory tests, a mood evaluation test, electrocardiograms (ECGs), and reported adverse experiences were monitored. Plasma levels were determined at two hours postdose. Results indicated no clinically relevant effects on vital signs, laboratory tests, ECGs, or mood evaluations. Dose proportionality was demonstrated. The incidence of total adverse effects (primarily somnolence and fatigue) after single-dose administation was 25 percent for placebo, 75 percent for 10 mg, and 81.8 percent for 20 mg. There was a relationship between incidence of adverse effects and dose, but no general correlation between plasma levels and severity of adverse experiences. The results indicate that ritanserin is safe and tolerable following acute administration of 10 mg and 20 mg oral doses.

Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 micrograms/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+/- 82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (+/- 68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (+/- 33.5) and 89.0 (+/- 23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension of the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400- and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.

The bioavailability of three different brands and three different dosage forms of doxycycline was studied in normal subjects. Single doses, equivalent to 200 mg of doxycycline, were administered to six subjects in a crossover design as the innovator's intravenous solution given orally (Treatment A), the innovator's capsule product (Treatment B), a noninnovator's capsule product (Treatment C), the innovator's oral suspension product (Treatment D), and a second noninnovator's capsule product (Treatment E). All dosage forms contained doxycycline as the hyclate, except the suspension which contained the nonhyclate form. Serum levels were determined periodically over 48 hr, and cumulative urinary excretion was measured concurrently over a 120-hr collection period. No statistically significant differences were observed in any in vivo indicator of bioequivalence when the three capsule products were compared. Consequently, they were judged to be bioequivalent. When these capsule products were compared to the oral solution, no statistically significant differences were observed. However, when the capsules and the suspension were compared, statistically significant differences were found in the rate of absorption. In vitro dissolution tests were also conducted on the three brands of capsules, and times required to achieve 50% dissolution showed rank-order correlation with corresponding absorption rate constants.

The bioavailability of seven commercial trisulfapyrimidine suspensions was studied in 14 adult male volunteers. Fifteen blood samples were collected over a 48‐hr period following administration of a 1‐g dose of each suspension. Serum was assayed for each component, (sulfadiazine, sulfamerazine, and sulfamethazine) by high‐pressure liquid chromatography. Analysis of variance indicated several significant differences among the seven commercial preparations with respect to C max , T max , and AUC for sulfadiazine, sulfamerazine, and sulfamethazine. The in vitro behavior of each suspension was then studied by the paddle method of the Food and Drug Administration. A 0.5‐ml sample was introduced into 900 ml of hydrochloric acid (2.2 × 10 −‐4 M ) at 37° and dissolved using a paddle speed of 25 rpm. Samples withdrawn at 15 and 30 min were analyzed by high‐pressure liquid chromatography, and the percent of sulfadiazine, sulfamerazine, and sulfamethazine was calculated. Significant correlation was obtained between an in vivo parameter ( C max for sulfadiazine) and an in vitro parameter (percent sulfadiazine dissolved in 30 min). Results indicate that this method is suitable for the in vitro screening of trisulfapyrimidine suspensions.

The stability-time profiles of the active ingredient of five generically equivalent brands of penicillin V potassium for oral solution, and of five generically equivalent brands of ampicillin for oral suspension, were studied. Three controlled conditions were employed-refrigerated, room and elevated temperature-and all the samples were assayed chemically for drug remaining at specific time intervals after reconstitution. The results showed that considerable variations in the initial concentrations of active component existed among the various ampicillin and penicillin products. In one penicillin product the official content requirement was not met. The data also showed that although the labels on each of the commerical penicillin products tested indicate that the reconstituted products may be stored in a refrigerator for 14 days without significant loss of potency, only one penicillin product still met 90% of label claim (minimal potency requirement of the United States Pharmacopeia for dry powder). All ampicillin products tested were stable when stored at the conditions recommended by the manufacturers, but the trihydrate forms exhibited greater stability than the anhydrous forms, probably because of the more rapid dissolution rate of anhydrous ampicillin.

A comparative bioavailability study was performed using two commercially available, chemically equivalent brands of sulfamethizole suspension. One gram of each suspension was administered to 12 different subjects following a completely randomized crossover design. Serum levels and derived pharmacokinetic parameters were compared statistically. There were no significant differences in the extent of sulfamethizole absorption from the two suspensions as evidenced by the area under the serum level--time curves. Significant differences (p less than 0.05) in the mean serum levels at 0.5 and 0.75 hr and differences in Cmax and tmax indicated that the absorption rate differed for the two products. In vitro tests including particle-size analysis and dissolution studies were performed. The size--frequency distribution of particles in the suspensions was studied using a resistance particle counter. The dissolution characteristics of the two products were studied using the Food and Drug Administration's paddle method and the spin-filter apparatus. Suspension A had a significantly greater amount of drug dissolved at 15 and 30 min using either method. It also had a greater percentage of particles at the smaller size range, indicating that the greater dissolution rate may be related directly to the decreased particle size. A comparison of the in vivo and in vitro results demonstrated a definite rank-order correlation between the dissolution performance of the two suspensions and the in vivo parameters reflecting the absorption rate. Suspension A had a greater amount of drug dissolved at 15 and 30 min and resulted in higher serum levels at 0.5 and 0.75 hr, a higher Cmax, and a shorter tmax.

The effect of altered urinary pH on the excretion of single doses of orally administered tetracycline hydrochloride and doxycycline hyclate was studied in humans. Alkalinization of the urine significantly enhanced the cumulative renal excretion of both tetracycline and doxycycline as compared to acidic urine treatments. Altered tubular reabsorption was assumed to have caused this effect, since tetracyclines have been shown to be more lipid soluble at their isoelectric pH (approximately the pH of the acidic urine treatment) as compared to more alkaline pHs. The renal clearance of doxycycline was significantly increased by urinary alkalinization.

A considerable amount of evidence indicates that the tetracyclines may produce their antibiotic action by inhibition of metalloflavoenzymes. In this investigation the inhibitory properties of a series of biologically active and inactive tetracycline analogs on the metalloflavoenzyme, NADH–cytochrome c oxidoreductase, were investigated. Those analogs capable of inhibiting the enzyme appeared to act, at least partially, by chelation of enzyme-bound metal. The site of chelation on the tetracycline molecule appeared to be the C-11 to C-12 chromophore, or the C-1, C-2, C-3 region involving the 2-carboxamide group of the tetracycline molecule. Both modification of the 2-carboxamide substituent and epimerization of the 4-dimethyl-amino group resulted in loss of inhibitory effect. This parallels known structure-antibiotic activity relationships for these compounds. Inactive isotetracycline, tetracycline methiodide, and dedimethylaminotetracycline were able to inhibit the enzyme at least as well as the parent tetracyclines. These compounds might lack antibiotic activity due to inability to enter bacterial cells.

Dimethyl sulfoxide (DMSO), 15 percent by weight, was incorporated into selected ointment bases containing 10 percent salicylic acid or 11.6 percent sodium salicylate. Percutaneous absorption was studied by determining salicylate blood levels in New Zealand white rabbits at regular intervals for 8 hr. following application of the ointment to the shaved intact skin and confinement by a specially designed bandage. DMSO in hydrophilic ointment and hydrophilic petrolatum produced more rapid drug absorption and higher salicylate blood levels than the control systems. Polyethylene glycol ointment and a polyoxyethylene (20) stearyl ether gel with DMSO did not produce any significant change in the absorption pattern. The salicylate blood levels obtained from percutaneous absorption of sodium salicylate in hydrophilic ointment containing DMSO were lower than with control systems. In the case of hydrophilic petrolatum, there were no significant differences in absorption patterns of sodium salicylate with or without DMSO. Sodium salicylate did not appear to be absorbed from polyethylene glycol ointment whether or not DMSO was included.

Hydrophilic ointment formulations containing salicylic acid were prepared at different pH levels by inclusion of phosphate buffers. Percutaneous salicylic acid absorption was studied by measuring salicylate blood levels in rabbits at 1.5-hr. intervals from 1.5 to 7.5 hr. after ointment application. The effect of 15% dimethyl sulfoxide in the various formulations was also determined. Formulations without dimethyl sulfoxide produced maximal blood concentrations at the highest pH level (10.78) and higher concentrations at the lowest pH (2.97) than at the intermediate ones (4.48, 6.80, 9.23). Proportionally higher concentration of undissociated species appeared to account for the increased absorption observed at the most acidic pH, while increased dissolution was probably responsible for the greater blood levels recorded at the most alkaline pH. Dimethyl sulfoxide produced a more rapid rate of salicylate absorption as well as greater peak blood levels at each pH. However, its influence on rate of absorption and on peak blood levels was less pronounced at the highest pH levels. This finding seems to indicate that the positive effect of dimethyl sulfoxide on percutaneous salicylate absorption is due in part to its ability to enhance the dissolution of salicylic acid.

The apparent partition coefficients between n-octyl alcohol and aqueous buffers (ranging from pH 2.1 to 8.5) were determined for several tetracyclines. Using the previously suggested microscopic dissociation constants for tetracycline, the relative amounts of each microscopic ionic form of tetracycline theoretically present at each pH were calculated. The zwitterionic form, −0+ (tricarbonyl methane system ionized, phenolic diketone moiety unionized, dimethylammonium cation postively charged), which was present in highest concentration in the pH range from 4 to 7, appeared to be the most lipid soluble form, its reduced polarity possibly resulting from an intramolecular type of ion-pair formation. Possible relationships between the biological activity of the various tetracycline analogs and their pH-octanol solubility profiles have been discussed.

The pH-partition behavior of the ampholyte antibiotics ampicillin, cephalexin, and cephaloglycin, using n-butanol or n-octanol as the lipid phase and aqueous phosphate buffers, was determined at 37° over a pH range of 4.9–7.9. By comparing the pH-partition behavior of these drugs with computer-generated plots of the concentration of their various ionic species as a function of pH, the anion was found to be the major partitioning species. Minimum partitioning occurred in the isoelectric region, suggesting that the zwitterion did not partition to a significant extent. The pH-partition behavior of L-phenylalanine, as a model ampholyte, was studied over a pH range of 2.0–8.9; although the L-phenylalanine cation partitioned into the lipid phase, the anion partitioned to a significantly greater extent, while the minimum partitioning in the isoelectric region indicated that the zwitterion was a poor partitioning species. Studies of surface activity as a function of antibiotic concentration in phosphate buffers showed that there is a relationship between the partitioning behavior of these antibiotics and either the reduction in surface tension or the resulting surface excess at the lipid-water interface. To account for the difference in the pH-partition behavior of the compounds employed in this study and the previously reported data for the tetracyclines, two general types of ampholytes capable of forming zwitterions should be considered, depending on whether or not significant amounts of uncharged species are present in the isoelectric region. Maximum partitioning into the lipid phase should occur if uncharged species is present in significant concentrations (e.g., tetracycline); the compounds in this study were of the other type and thus showed reduced partitioning in the isoelectric pH region.

The in vivo effect on aspirin absorption of a potentially more palatable form of activated charcoal was compared to that of a simple aqueous slurry of activated charcoal. The experimental formulation consisted of 20.0 g of activated charcoal, 2.25 g of carboxymethylcellulose (CMC) and 42.8 ml of water; it was tested with and without chocolate syrup as a flavoring agent added just prior to administration. Six subjects were treated in crossover fashion following an aspirin dose of 972 mg. Total urinary excretion of salicylate was measured over 48 hours. Although all three treatments appeared to be effective in reducing the rate and extent of aspirin absorption, the slurry was significantly more effective in reducing the total amount absorbed than the charcoal-CMC gel with chocolate syrup. The slight difference in effectiveness between the gel formulation with and without the chocolate syrup was not significant.

Percutaneous absorption of salicylic acid was measured by blood levels in 20 rabbits, each given four runs at 1-week intervals. Dimethyl sulfoxide was added to the ointment in two runs (Runs 1 and 3 for half the animals, Runs 2 and 4 for the others), thus forming a crossover design with one repetition of each condition. The four successive runs caused a progressive and statistically, highly reliable decrease in percutaneous absorption. This effect of prior exposure increased during successive 1.5-hr, time intervals, from 1.5 to 7.5 hr., and showed no reliable interaction with dimethyl sulfoxide and with pH. A large effect of prior exposure was the increased stability of the salicylate absorption scores and, thereby, greater reliability of the experimental effects, shown by much lower residual terms in the analysis of variance for Runs 3 and 4 than for 1 and 2. Skin dehydration and decreased emotional arousal are possible explanations for the slower and more consistent rate of percutaneous absorption after prior exposure to the test situation.

All 50 states either permit or require a pharmacist to substitute a generic drug for a prescribed brand-name drug unless the physician specifically notes on the prescription form that substitution is not to be made. In certain critical therapeutic categories and for certain patient populations, each substitution poses the risks of treatment failure and of increased toxicity. The therapeutic categories include cardiovascular drugs, psychotropic agents, and anticonvulsants. Additional potential therapeutic categories include cardiovascular drugs, psychotropic agents, and anticonvulsants. Additional potential therapeutic categories include low-dose oral contraceptives, bronchodilating agents, oral diuretics, and oral anticoagulants. The populations at risk include debilitated or elderly patients with abnormal gastrointestinal, renal, or hepatic function. The FDA's approach to approval of generic drugs, based primarily on the demonstration of bioequivalence, is considered by many professionals as likely to result in excessive variability among treated patients. Depending on the particular rule defining bioequivalence, indiscriminate switching among generic versions of a brand-name drug potentially could result in 40% to 60% differences in rate or extent of absorption. For drugs that require careful titration to assure efficacy and lack of toxicity, such variability can have important consequences. The FDA is now reviewing its policies for approval of generic drugs. Until the matter is resolved, however, caution should be exercised when prescribing or dispensing drugs that can be substituted. Indiscriminate switching among generic products should be avoided, especially for drugs in the critical therapeutic categories and for drugs prescribed for elderly or debilitated patients.

The rectal absorption of acetaminophen from an aqueous solution and from several polyethylene glycol base dosage forms was studied in six human subjects using urinary excretion measurements. A relationship was observed between acetaminophen bioavailability and the dielectric properties of the vehicles utilized. The in vitro dissolution rates of acetaminophen in these dosage forms were also studied and were somewhat related to the time of occurrence of the maximum urinary excretion rate.

Relative bioavailability of the investigational gastrointestinal stimulant agent cisapride after oral administration was determined in healthy men. Treatments administered were (A) two 5-mg tablets; (B) one 10-mg tablet; (C) 10 mL of a 1-mg/mL suspension; and (D) 10 mL of a 1-mg/mL aqueous reference solution. The study had a randomized four-way, crossover design; drug administration was followed by a standard breakfast. Plasma cisapride concentrations in blood samples drawn over 48 hours were measured by high-performance liquid chromatography. Individual and mean values for bioavailability parameters were subjected to analysis of variance followed by multiple comparison testing. Time to maximum concentration was shortest after administration of the solution. There was a significant difference in mean peak plasma concentrations between treatment A (48.8 +/- 12.8 ng/mL) and treatment D (41.6 +/- 10.6 ng/mL), with treatment A producing a 17.3% higher peak concentration. No significant differences between treatments were found for area under the plasma concentration-time curve. The overall mean elimination half-life was 7.01 hours. The results of the study indicate that the tablet and suspension dosage forms of cisapride are bioequivalent to the reference solution.

A UV method is described for measuring total sulfa drug concentration in dissolution samples. This in vitro measurement was found to correlate well with several in vivo parameters obtained after administration of commercial trisulfapyrimidine suspensions to humans. The UV method, which is rapid, simple, inexpensive and easily automated, is recommended for studying the dissolution of trisulfapyrimidine suspensions.

A simple and rapid high-pressure liquid chromatographic method was developed for the determination of sulfadiazine, sulfamerazine, and sulfamethazine in human serum. After the trichloroacetic acid precipitation of the serum proteins, an aliquot of the supernate is injected into a high-pressure liquid chromatograph equipped with a reversed-phase microparticulate column and a fixed wavelength UV detector. For each of the three components of trisulfapyrimidines, a linear calibration curve was observed in the 1-30-microgram/ml range, with the precision of the assay estimated to be +/- 2% (RSD). Preliminary pharmacokinetic data are also presented.

The phenothiazines have exhibited a history of problems associated with the bioequivalence of solid oral dosage forms. The more recent availability of chemically equivalent forms of thioridazine has raised new and interesting questions about the appropriateness of generic product interchange, even among brands that have been designated “therapeutically equivalent” by the Food and Drug Administration. The scrutiny that has accompanied the consideration of thioridazine products for inclusion into various state generic substitution formularies has offered an opportunity to examine issues involving bioequivalency in considerable detail. Specific bioequivalency concerns relate to: Correct analysis of drug in biological fluids; the importance of evaluating active metabolites; single-dose vs. multiple-dose crossover studies; appropriate statistical power analysis; the “70/70” rule, and comparison of product variabilities. Examples of problems are cited to illustrate that significant questions still remain about the appropriate factors that should be used to establish bioequivalency.

Piroxicam is a widely used nonsteroidal antiinflammatory drug available worldwide under various trade names by several manufacturers. Only one brand of piroxicam (Feldene) is currently marketed in the U.S., and the United States Pharmacopeial Convention established an official dissolution requirement for piroxicam in 1985. The purpose of this study was to evaluate and compare the dissolution performance of several internationally available piroxicam products using the United States Pharmacopeia (USP) dissolution test for piroxicam capsules. Of 25 brands of piroxicam capsules evaluated, 72 percent of the brands failed to meet the USP requirement, several by a wide margin. Although there is no specific USP dissolution test for tablets, the test for capsules was applied to five different brands of piroxicam tablets, and 80 percent of the tablet brands tested failed to meet the USP requirement. Although comparative bioavailability studies would be required to establish any definitive relationship between dissolution test performance and bioavailability, the failure of most of these products to meet the USP requirement for dissolution indicates formulation differences that could result in altered bioavailability. The substantial differences in dissolution performance observed among the piroxicam oral dosage forms tested have implications concerning the equivalency and standards of multisource products available on the international market, and should be taken into account by health care providers worldwide.

A comparative bioavailability study was performed using four commercially available, chemically equivalent brands of quinidine sulfate tablets. Two 200-mg tablets were administered to 11 different subjects following a completely randomized crossover design. Serum levels, urinary excretion data, and derived pharmacokinetic parameters were compared statistically. There were no statistical differences in the extent of quinidine absorption from the four brands of tablets as evidenced by the cumulative urinary excretion values and the areas under the serum level–time curves. Significant differences in the mean serum levels at 0.5 and 1 hr and differences in the peak times and absorption rate constants indicate that there was a difference in the absorption rate between Treatments A and D and C and D. A significant difference in the peak times also was noted for Treatments B and C. When mean disintegration times for the four tablet formulations were compared with their values for k a , t max , and mean serum levels at 0.5 and 1 hr, rank-order correlations were observed. A considerable degree of variability in quinidine elimination was noted, with half-life values ranging from 2.71 to 8.12 hr (mean half-life of 5.36 hr).