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To address the shortage of research-trained pharmaceutical scientists (or doctor of pharmacy [Pharm.D.] scientists), a 2-day pharmacy research conference titled "Pharm.D. Pathways to Biomedical Research" was convened on December 13-14, 2006, at the National Institutes of Health (NIH) campus (Bethesda, MD). The workshop included invited speakers and participants from academia, industry, and government. Forty-two pharmacy schools were represented, including deans and clinical pharmaceutical scientists with current NIH funding. In addition, several pharmacy professional organizations were represented--American Association of Colleges of Pharmacy, American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and the Accreditation Council on Pharmaceutical Education. The workshop was divided into three sessions followed by breakout discussion groups: the first session focused on presentations by leading pharmaceutical scientists who described their path to success; the second session examined the NIH grant system, particularly as it relates to training opportunities in biomedical research and funding mechanisms; and the third session addressed biomedical research education and training from the perspective of scientific societies and academia. We summarize the discussions and findings from the workshop and highlight some important considerations for the future of research in the pharmacy community. This report also puts forth recommendations for educating future pharmaceutical scientists.

I skate to where the puck is going to be, not to where it has been. --Wayne Gretzky, Edmonton Oilers, Mid-1980s In the early 1990s, the American Association of Colleges of Pharmacy (AACP), under the joint auspices of the Councils of Faculties and Deans, published an extensive series of excellent invited manuscripts known as Academic Management System. (1) This publication served many deans, department heads, and others as a blueprint to help guide the structure and operations of schools and colleges of pharmacy through much of the past 2 decades. Highly experienced pharmacy administrators and faculty members authored key chapters on management; planning; human, fiscal and capital resources; operations; and academic affairs; and all of the chapters were reviewed by experienced colleagues and included helpful case studies. Although much has changed in the academy in the nearly 20 years since this series appeared, many if not most of the basic principles and practices discussed in these chapters remain relevant today. I had the privilege of authoring the chapter on leadership as the newly appointed at the University of Kentucky. After recently rereading and reflecting on the dramatic changes in the health care and academic environments prompted me to reflect on the challenges and opportunities facing leaders of schools and colleges of pharmacy today. In an overarching sense, the role of the dean in higher education has not changed much over the years. Those role(s) are (1) to work with faculty and other stakeholders to establish the vision and direction of the program; (2) to recruit and retain the best possible faculty and staff; (3) to accumulate the necessary resources to accomplish the major goals; and (4) to mentor younger colleagues while facilitating organizational renewal and succession planning. Yet when one looks at the challenges and rapidly changing circumstances that face universities today, every element of those 4 basic responsibilities seems to take on a different level of import and urgency than it had even a few short years ago. (2) What is even more obvious is that this rapid pace of change, together with globalization and other economic pressures, will continue to make deanships more challenging and may lead to decreasing tenures for deans--as is already the case for university department chairs, presidents, and provosts, as well as leaders of major business and nonprofit organizations. While the data are soft, the tenure of medical school deans has steadily decreased from 1940 to 1992. (3) The average tenure for deans dropped from 6.7 years in the 1940-1959 time period, to 5.8 years in 1960-1979, and to 3.5 years in the 1980s and early 1990s. (3) This has increased to between 5 and 6 years on average today. I surveyed all schools and colleges of pharmacy established before 1985 and found similar results for pharmacy deans (Table 1). This trend has been observed in senior academic administrative positions and raises concerns about continuity and succession planning, as well as having implications for the background and training leaders will require so that they can adapt and successfully operate in a much more demanding and fast-paced environment. These factors, combined with the rapidly expanding number of schools, portends the need to identify and nurture many more individuals willing and able to assume deanships in the years ahead. The Pharmacy Deanship in the 1980s and Early 1990s At the risk of overly generalizing, universities were much more predictable and stable institutions in the 1990s than they are today. Applications from prospective students and yearly enrollments held steady. State governments were generally supportive of higher education, with fewer concerns about value or accountability. The tenure of presidents, vice presidents, and provosts was significantly longer. The call for health care reform had not reached much urgency. Shortages of pharmacists had not materialized. …

Dissolution tests have been in use in the pharmaceutical industry for over 20 years, and they are official in The United States Pharmacopeia since the early 1960s. The dissolution test, reviewed primarily as a quality control tool, replaced the use of disintegration tests which had been official in The United States Pharmacopeia since 1950. Refinements in the dissolution test equipment and methodology have occurred over the years in order to enhance its relevance. The Subcommittees of the USP Committee of Revision dealing with these issues have developed and refined compendial dissolution standards and policies for conventional solid-oral dosage forms and modified-release dosage forms.

a The University of Iowa, 115 S. Grand Avenue, Iowa City, IA 52242 b The Ohio State University, 500 West 12 Avenue, Columbus, OH 43210-1291 c Creighton University, 2500 California Plaza, Omaha, NE 68178-0104 d Auburn University, 217 Walker Building, Auburn University, AL 36849-5501 e The University of Mississippi, PO Box 1848, University, MS 386551848 f Kaiser Permanente, 16601 E. Centretech Parkway, Aurora, CO 80011 g American Association of Colleges of Pharmacy, 1426 Prince Street, Alexandria, VA 22314-2841

Gentamicin concentrations in appendix tissue, serum, and peritoneal fluid were obtained in suspected cases of gangrenous or perforated appendicitis. Despite widely ranging gentamicin concentrations, no infectious complications developed. Correlations were made between the pathologic state of the tissue and the tissue gentamicin concentrations. Correlations were also made with tissue gentamicin concentrations and the time after the antibiotic dose to the time of sampling.

Kinetics of and clinical responses to N-acetylprocainamide (NAPA) were evaluated in 10 patients with chronic ventricular arrhythmias who had not responded to usual doses of currently available antiarrhythmic drugs. Kinetic data analysis was by measured NAPA concentrations (n = 149) collected during repeated dosing. Response was evaluated with serial 24-hr ambulatory ECGs. An a priori kinetic model based on earlier studies predicted NAPA concentrations well (r =0.94, SEE = 3.6 mg/l). The capability for defining patient-specific estimates for drug disposition with six or seven serum concentrations measured at the outset of therapy was subsequently confirmed with larger data sets from the same patients. Mean values for elimination rate (0.082 hr−1 ± 0.017) and volume of distribution (1.25 l/kg ± 0.28) were of the same order as in earlier single-dose studies. A substantial degree of interpatient and intrapatient variability in the absorption rate for NAPA was observed. NAPA was not found to be clinically effective in any of the 10 patients, although two patients demonstrated a >70% reduction in frequency of premature ventricular contractions. There were adverse effects in all patients, which frequently required dose reduction or cessation of therapy. In this group of patients with resistant arrhythmias, NAPA was no more effective than baseline therapy, and adverse effects often limited complete evaluation. The kinetic analysis demonstrated the feasibility of a strategy for developing patient-specific kinetic models that may have applications to other antiarrhythmic drugs. Clinical Pharmacology and Therapeutics (1982) 32, 378–386; doi:10.1038/clpt.1982.175

A patient case is presented to illustrate a systematic approach to the assessment and modification of theophylline therapy by the pharmacist using serum level analysis. The pharmacist is a pulmonary disease service is responsible for: (1) determining relevant aspects of the patient's clinical condition; (2) defining an initial theophylline administration regimen, including route, dose and schedule; (3) estimating expected theophylline levels based upon the regimen and known or assumed parameters of theophylline in the patient; (4) defining and recommending number and timing of serum samples to be drawn for analysis; (5) obtaining laboratory results and comparing with preliminary estimations; (6) assessing clinical response or toxicity, or both; and (7) recommending appropriate modifications in the theophylline regimen.

In an attempt to compare the efficacy of various 5-fluorouracil (5-FU) regimens, we studied the kinetics of 18F-labeled and unlabeled 5-FU in rats. 18F-5-FU was synthesized in our laboratory and was administered in tracer doses to Fischer rats bearing either the 13762 or the R3230 mammary adenocarcinoma, and to Sprague-Dawley rats bearing the Walker-256 carcinosarcoma, with or without pre-treatment with a therapeutic dose of unlabeled 5-FU. In addition, the non-radioactive 5-FU was administered to control rats of both strains. All animals were followed for 70 min either by measuring their 18F blood levels continuously using an extracorporeal blood-loop, or by determining their 5-FU blood levels at discrete time intervals. The biphasic kinetic profile was characterized by determining α and β rate constants and their corresponding half-lives. Differences in 18F elimination, as measured by the area under the curve during the elimination phase, were observed between the pre-treated 13762-bearing rats and the untreated group bearing the same tumor. as well as the pre-treated non-tumored controls and both W-256-bearing groups. Such differences could reveal changes in the ability of those rats to metabolize 5-FU, and hence correlate to the level of active metabolite(s) available to their tumor sites.

A multitude of factors influence the prescribing, dosing, and clinical monitoring of long-term drug therapy in elderly patients. These include life-style and environment, possible multiple disease states and concomitant medications, compliance, and continuous changes in physiology, all of which can—with advancing age—gradually alter the pharmacodynamics and pharmacokinetics of drugs. The physiologic changes associated with aging that can affect the absorption, distribution, excretion, and metabolism of drugs are reviewed and related to the clinical use of several drugs that are widely used in elderly patients. Important clinical factors may also magnify or counteract the physiologic changes that occur with respect to altered drug response. Finally, the pharmacokinetic properties of the available oral hypoglycemic agents are described as they relate to selection of an optimal drug in elderly diabetic patients.

Developments in the analysis and pharmacokinetics of lithium, and the role of the pharmacist in the management of lithium therapy in affective disorders, are described. Research showing that lithium levels in the brain may be better predicted from erythrocyte lithium levels than plasma levels is reviewed. Also reviewed is lithium kinetics in affective disorders. The pharmacist (1) determines relevant aspects of the patient's condition, (2) develops an appropriate blood sampling schedule, (3) initiates and maintains a serial lithium erythrocyte and plasma patient profile, (4) evaluates erythrocyte and serum levels in relation to established criteria to provide a basis for differential diagnosis of the patient, and (5) individualizes lithium dosage and schedules. Four cases are used to illustrate this approach. It is suggested that outpatient mental health clinics would be likely settings for the further development of this clinical role.

Twenty patients with solid tumors received 30 mg/M2 of adriamycin. Various tissue samples were intraoperatively obtained from 18 patients, about 1.5--5 hours after an intravenous (IV) bolus dose. Normal liver showed the highest levels of adriamycin uptake (2.3--19.8 micrograms/g); lymph nodes were second; muscle and bone marrow, next; fat and skin had the lowest adriamycin uptake (0.04--0.40 microgram/g). Tumor tissue, excluding that with much necrosis and hemorrhaging, had adriamycin concentrations which approximated those of the liver (1.1--9.2 micrograms/g). Six patients, all with hepatic malignancies, had prolonged plasma concentration studies after IV administration; 5 also had adriamycin administered directly into the hepatic artery catheter. Adriamycin-plasma-time courses were similar, whether the drug was administered by bolus directly into the hepatic artery or peripheral vein. The concentration of metabolites after hepatic intraarterial administration was definitely higher than that after IV administration. Patients with hepatic dysfunction had delayed plasma clearance and secondarily elevated levels approximately 160 and 300 minutes after administration.

Metoclopramide has recently been approved at dose levels of 1 to 2 mg/kg for the treatment of nausea and vomiting resulting from cancer chemotherapeutic agents. A rapid, sensitive reverse phase HPLC quantitative procedure for metoclopramide in serum is described. The method involves a single-step extraction of metoclopramide and disopyramide (internal standard) from alkalinized serum into benzene and utilizes a reverse-phase C-8 system with a mobile phase of 11:22:66, methanol: acetonitrile: pH 3.7 acetate buffer, and UV detection at 268 nm. The method is highly reproducible and has a limit of sensitivity of 2.5 ng/ml from a 2.0 ml serum sample. The method has been successfully applied to clinical pharmacokinetic studies involving administration of IV oral metoclopramide to cancer patients receiving highly emetogenic cis-diamminedichloroplatinum.

A rapid, specific, and sensitive GLC assay for caffeine in plasma was developed utilizing alkali flame-ionization detection. The procedure involves the addition of mepivacaine as an internal standard, alkalinization of the sample, and extraction with chloroform. Peak height ratio measurements produced linear standard curves in the 0.25-10.0-microgram/ml range. Absolute sensitivity from a 1.0-ml plasma sample was 0.1 microgram/ml. The relative standard deviation of a 2.0-microgram/ml pooled plasma standard run repeatedly over several months was 5.2%. The method is applicable to time-concentration studies in human and animal plasma following typical oral doses of caffeine.

Total penetration of 5-fluorouracil (FU) through human and hairless mouse skin was measured in vitro and the results were compared using radioactively labelled drug and a gas chromatographic method specific for the free FU molecule. Both methods were used to determine whether metabolism, either in the skin during penetration or in the penetration wells, could have affected the percent penetration as calculated by the radioactivity method. The results indicate significantly greater drug penetration in the mouse samples using both methods of detection, with somewhat greater variations between identical samples occurring with the chromatographic method. The percent penetrating the human samples, approximately 12 percent after 20 hr, agreed with the previously reported in vivo data. These studies indicate that further in vitro studies may be useful to study the factors affecting the penetration of FU when applied topically in a variety of skin diseases.

The effect of diltiazem on digoxin serum concentration was evaluated in 9 patients who had been treated chronically for heart disease with digoxin, 0.25 mg/day. The indications for digoxin therapy were arrhythmias in 5 patients and mild heart failure in the other 4. Renal digoxin clearance was also evaluated in 8 of these patients. Serum digoxin concentration was measured at control, 7 +/- 2 days after initiation of 120 mg/day of diltiazem and 11 +/- 5 days after increasing the dose of diltiazem to 240 mg/day. Serum digoxin concentration was 0.9 +/- 0.4 ng/ml at control, 0.8 +/- 0.4 ng/ml with 120 mg/day of diltiazem, and 0.8 +/- 0.3 ng/ml during therapy with 240 mg/day. The differences between these values were not significant. Renal digoxin clearance also did not show a significant change after diltiazem therapy (44 +/- 15 ml/min before diltiazem and 46 +/- 13 ml/min with 240 mg/day of diltiazem). This study shows no effect of diltiazem in doses of 120 to 240 mg/day on serum digoxin concentration or renal digoxin clearance in patients who are treated chronically for heart disease with digoxin. In this dose range, diltiazem has advantages over verapamil, which markedly elevates digoxin levels.

Group theory was applied to a wide variety of toxic substances, drugs, and endogenous organic compounds to test the apparent empirical relationship between toxicity of a molecule and its degree of molecular symmetry. Many compounds in each classification were analyzed and separated into individual symmetry groups using “space-filling” molecular models. With few exceptions, an apparent relationship was noted between each symmetry group and the relative toxicities. A brief introduction to group theory is presented as well as the rationale and implications of these observations.

The rate of absorption and plasma concentrations of lidocaine were determined in 15 supine patients under general anesthesia following either endotracheal spray of 200 mg. (average 3.3 mg./kg.) of 4 percent lidocaine hydrochloride solution with a special cannula (LTA Kit, Abbott) (N = 6) or 1 mg./kg. of 2 percent lidocaine solution as an intravenous bolus injection (N = 9). In the 6 patients after endotracheal spray, peak plasma lidocaine levels were reached at 15 to 20 minutes (mean 3.54 plus or minus 0.76 S.E. mug./ml. at 20 minutes). In the 9 patients given 1 mg./kg. intravenously, dose peak concentrations were reached within 2 minutes (mean 5.63 plus or minus 0.18 S.E. mug./ml. at 2 minutes). Plasma concentrations of lidocaine in both groups were within nontoxic ranges.

Simultaneous measurement of plasma, RBC, and plasma lithium concentrations took place with 17 inpatients chronically treated with lithium, at various times after the last lithium dose. RBC lithium levels were significantly higher than CSF lithium levels. Specimens drawn 10 or more hours after the last dose showed higher RBC and CSF lithium and lower plasma lithium than specimens drawn 4 or less hours after the last lithium dose. None of the lithium measurements differentiated manic-depressives from schizophrenics or schizoaffectives. Plasma, RBC, and CSF lithium all intercorrelated highly and equally.

We performed ophthalmologic examinations on 127 subjects with or at risk for human immunodeficiency virus (HIV) infection over a one-year period to determine the prevalence and significance of retinal cotton-wool spots and hemorrhages (AIDS-related retinal microvasculopathy). Of 26 asymptomatic homosexual men, of whom 13 were HIV seronegative and 13 were HIV seropositive, none manifested this retinopathy. Three of 34 patients (9%) with AIDS-related complex and 29 of 67 patients (43%) with AIDS manifested retinopathy on the initial examination. This difference in the prevalence of retinopathy between groups was statistically significant (P less than .05). Patients with AIDS demonstrated 7.2 times greater odds of manifesting retinopathy than patients with AIDS-related complex (P less than .05). Within the group of patients with AIDS, the T helper (CD4) to suppressor (CD8) cell ratio was significantly associated with retinopathy at the initial ocular examination. The CD4:CD8 ratio of the total group of AIDS and AIDS-related complex patients with retinopathy was significantly lower than that of patients without retinopathy (P less than .05). There was no significant association between retinopathy and any specific past or concurrent opportunistic infection or neoplasm. The presence of retinopathy was not associated with symptoms in any patient. The lesions of AIDS-related retinal microvasculopathy may be an important finding in the evaluation of patients suspected to have HIV-related disease.

Eflornithine [2-(difluoromethyl)-DL-ornithine monohydrochloride, monohydrate; DFMO] is an ornithine decarboxylase inhibitor used to treat Pneumocystis carinii pneumonia (PCP) in AIDS patients unresponsive or intolerant to conventional drug therapy. A reversed-phase HPLC method utilizing precolumn dansylation is described which permits the analysis of DFMO in serum of AIDS patients in support of pharmacokinetic studies. Norvaline (2-amino valeric acid) was added as the internal standard and the sample was extracted with three portions of ice-cold 80% ethanol. The supernatants were evaporated in a vacuum oven at 50 degrees C, and the residue was dissolved in base and derivatized at 25 degrees C for 4 h in the dark using dansyl chloride in acetone. Dilute base was then added and 25 to 50 microL was injected into the HPLC. Chromatography was performed on a C-8, 15-cm column with a linear gradient from a 95:5 solution of 10 mM pH 4 acetate buffer and THF, to a 90:10 solution of acetonitrile and THF over a period of 28 min. Detection was by UV at 330 nm, and DFMO and norvaline eluted at 14.7 and 17.7 min, respectively. The method was linear over a range of 5 to 950 micrograms/mL, and replicate analyses of a 25-micrograms/mL control specimen produced a between-run coefficient of variation of 6%. No interferences were encountered in a variety of patient and normal serum blanks.

Specific assay procedures were developed to measure plasma concentrations of (plus or minus)-1, 2-bis(3, 5-dioxopiperazinyl) propane (1) by GLC using flame-ionization detection with a sensitivity limit of 5 mug/ml and by GLC-mass fragmentography with a sensitivity limit of 0.2 mug/ml. Applicability of the assay procedures was demonstrated in rats, rabbits, and humans. Plasma concentration-time curves of total 14-C activity and intact I was obtained in rats and rabbits following oral and intravenous administration of 14-C-I. Plasma elimination half-lives of I in the first 2 hr following intravenous doses in rats were 40 and 45 min in two rats. Plasma levels of I were measured over 6 hr after an intravenous dose in rabbits and followed a two-compartment open model with a terminal loglinear plasma half-life of 85 min. Significantly higher total 14-C levels compared to intact I plasma concentrations indicated rapid biotransformation in both rats and rabbits to unknown metabolites. The oral bioavailability appeared to be limited in both species relative to intravenous administration. Two patients receiving 3 g I/m-2 in tablets orally showed plasma levels of I similar to those obtained after oral doses in rats and rabbits, with peak concentrations at 2 hr after the dose (3.8 mug/ml) and with still measurable levels 12 hr after the dose (0.4 mug/ml).

The existence of a threshold serum metoclopramide level above which total protection from cisplatin-induced vomiting is more likely to occur has been proposed. We monitored serum metoclopramide levels prior to the third metoclopramide dose in the first cisplatin treatment cycle in patients receiving metoclopramide 2 mg/kg x 4 as part of a randomized double-blind cross-over study comparing single-agent metoclopramide with combination metoclopramide and dexamethasone. Serum samples from 35 patients (17 receiving single-agent metoclopramide and 18 receiving the combination) were analyzed using reverse-phase high-pressure liquid chromatography (HPLC). A wide variation in metoclopramide levels was observed (range 273-3380 ng/ml). Serum levels obtained from the same patient on multiple treatment cycles were well correlated, and the addition of dexamethasone did not alter serum metoclopramide levels. No threshold level could be identified for the two groups (single-agent or combination antiemetic therapy) considered individually or considered together. However, significantly more vomiting episodes and a lower incidence of total protection were noted in patients with metoclopramide levels above 1469 ng/ml receiving metoclopramide alone. This effect was nullified in the combination antiemetic group. Our data do not support a directly proportional relationship between serum metoclopramide level and antiemetic protection. However, a non-linear relationship with a possible agonist/antagonist effect is suggested.

Group theory was applied to a wide variety of toxic substances, drugs, and endogenous organic compounds to test the apparent empirical relationship between toxicity of a molecule and its degree of molecular symmetry. Many compounds in each classification were analyzed and separated into individual symmetry groups using “space-filling” molecular models. With few exceptions, an apparent relationship was noted between each symmetry group and the relative toxicities. A brief introduction to group theory is presented as well as the rationale and implications of these observations.

On the basis of a simple model of 1:1 complex formation between planar molecules, this equation was derived: △G°u = A(G°SL — G°MS —G°ML),where △G°u is the standard unitary free energy change for complex formation, A is the area of overlap in the plane-to-plane interaction between the two molecules, and G°IJ is a free energy of interaction per unit area between I and J (S, L, and M represent substrate, ligand, and medium.) If the parenthesized term is roughly constant for a series of substrates and ligands in a constant medium, it is suggested that the quantity G°SL does not play a major role, and that the complex stability is primarily con-trolled by repulsive solvent interaction terms (G°MS and G°ML). It follows that the system will assume an orientation of S and L such as to maximize A. Therefore, maximal overlap areas were estimated for 18 neutral and 32 ionic complexes. A substantial improvement in the area correlation was obtained, and the observation was made that there is no significant difference between the average behavior of neutral and charged complexes. The maximal overlap concept provides a general “first-order” description of molecular complex formation in aqueous solution. Deviations from the line are significant and may be associated with specific structure-stability relationships. Application of the maximal overlap approach leads to average complex structures without introducing arbitrary assumptions about specific group interactions. The structures thus generated are consistent with the chemical reactivity of the complexes.

A rapid, sensitive GLC method of analysis for 5-fluorouracil was developed to follow the disposition of the drug in patients on 5-fluorouracil therapy. The free drug is removed from aqueous biological samples in a single extraction step, derivatized by silylation, and chromatographed using flame-ionization detection. An internal standard is utilized to quantitate the results. The procedure is rapid, sensitive (0.2 mcg./ml. plasma), specific for the intact 5-fluorouracil molecule, and suitable to support pharmacokinetic studies of 5-fluorouracil in animals and humans.

In the article by McDermed et al "Clinical Pharmacokinetics of High-Dose Metoclopramide in Cancer Patients Receiving Cisplatin Therapy" (Journal of Clinical Oncology 3:1400–1408, 1985), an error was made in the second column on page 1401 that altered the meaning of an equation. The correct equation appears below. Please see the PDF for Equation.