Model-based drug development: a rational approach to efficiently accelerate drug development.

The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In today's development paradigm, late-stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model-based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.

Paradoxical arterial embolism involving both upper extremities in a patient with pulmonary embolism and a patent foramen ovale.

Paradoxical embolization is an uncommon but devastating complication of pulmonary embolism (PE). Awareness of this complication with prompt recognition and treatment could serve to preclude significant disability and death. Described is a case of PE associated with paradoxical embolism to the arteries of both upper extremities. While patent foramen ovale (PFO) is common, paradoxical embolism is infrequent but can involve almost any artery of the body. Discussed are the risk factors, clinical presentations, and diagnostic and treatment options for paradoxical embolism. Awareness of the potential for paradoxical embolization in patients with PE is essential to its prompt recognition and treatment.

Model-based drug development.

The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.

Evaluation of the Intelisite capsule to deliver theophylline and frusemide tablets to the small intestine and colon.

The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.

Effect of dofetilide on the pharmacokinetics of digoxin.

The effect of dofetilide on the steady-state pharmacokinetics of digoxin was evaluated in a randomized, double-blind study. Five days of dofetilide treatment did not significantly affect steady-state pharmacokinetic variables of digoxin compared with placebo; therefore, the use of dofetilide does not necessitate an adjustment in digoxin dose to maintain therapeutic digoxin levels.

The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing.

AIMS: The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily. METHODS: Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 microg (n = 8), 1500 microg (n = 8), or 2500 microg (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two-way crossover for each subject and separated by at least a 6 day washout period. RESULTS: Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. Ctrough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (Cmax) and the area under the concentration vs time curve (AUC(0,tau) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. Cmax occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose-dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml-1) than on day 5 (ranging from 9.9 to 12. 8 ms/ng ml(-1). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.

Involvement of conserved aspartate and glutamate residues in the catalysis and substrate binding of maize starch synthase.

Chemical modification of maize starch synthase IIb-2 (SSIIb-2) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), which modifies acidic amino acid residues, resulted in a time- and concentration-dependent inactivation of SSIIb-2. ADPGlc was found to completely protect SSIIb-2 from inactivation by EDAC. These results suggest that glutamate or aspartate is important for SS activity. On the basis of the sequence identity of SS, conserved acidic amino acids were mutagenized to identify the specific amino acid residues important for SS activity. Three amino acids (D21, D139, and E391) were found to be important for SS activity. D21N showed 4% of the wild-type enzyme activity and a 10-fold decrease in the affinity for ADPGlc, while the conservative change from D21 to E resulted in a decrease in V(max) and no change in affinity for ADPGlc, suggesting that the negative charge is important for ADPGlc binding. When sites D139 and E391 were changed to their respective amide form, no SS activity was detected. With the conservative change, D139E showed a decrease in V(max) and no changes in apparent K(m) for substrates. E391D showed a 9-fold increase in K(m) for ADPGlc, a 12-fold increase in apparent K(m) for glycogen, and a 4-fold increase in apparent K(m) for amylopectin. The circular dichroism analysis indicates that these kinetic changes may not be due to a major conformation change in the protein. These results provide the first evidence that the conserved aspartate and glutamate residues could be involved in the catalysis or substrate binding of SS.

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide.

AIMS: The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. METHODS: Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 microg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. RESULTS: Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml-1 increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. CONCLUSIONS: These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.

Analysis of purified maize starch synthases IIa and IIb: SS isoforms can be distinguished based on their kinetic properties.

Since starch synthases IIa (SSIIa) and SSIIb have not been purified from plant tissue, their structure-function relationships have not been well characterized. Therefore, we have expressed these SS genes in Escherichia coli, purified them to apparent homogeneity, and studied their kinetic properties. In addition, the N-terminally truncated forms of these enzymes were studied in an attempt to understand the function of the diverse N-terminal sequences in SS. Our results show that, like SSI, the N-terminal extensions of SSIIa and SSIIb are not essential for catalytic activity and no extensive changes in their kinetic properties are observed upon their N-terminal truncation. Each isoform of SS can be distinguished based on its kinetic properties. Maize SSI and maize SSIIb exhibit higher Vmax with glycogen as a primer, while the converse is true for SSIIa. However, the specific activity of SSIIb is at least two- to threefold higher than that for either SSI or SSIIa. Although SSIIb exhibits the highest maximal velocity of the isoforms compared, its apparent affinity for primer is twofold lower than the affinity of SSI and SSIIa for primer. Perhaps these differences in primer affinity, primer preference, and maximal velocities all contribute in some way to the different structure(s) of starch during its synthesis. Expression and purification of maize SS has now provided us a useful tool to address the role(s) of SS in starch synthesis and starch structure.

Case study of institution-building by nurse Bertha Wright and colleagues.

PURPOSE: To illuminate the history of nurses' participation in institution-building in the early 1900s, using the Baby Hospital in Oakland, California (now called Children's Hospital Oakland) as a case. DESIGN: Historical research using a framework of women's history theory focused on the women who founded Oakland's Baby Hospital, 1910-1930. METHOD: Data collection included studying original sources, archival material, and interviews. Data evaluation included external criticism for authenticity and genuineness, and internal criticism for accuracy and bias. FINDINGS: In 1912, nurse Bertha Wright and social worker Mabel Weed, with a circle of community women, including Jessica Peixotto and Jean Howard McDuffie, established the Baby Hospital. Their activism included home visits, education, research, publications, political lobbying, and state policy and program development. At the center of this activity, was the lifelong commitment of Wright and Weed, who created new definitions of family. With social changes in the late 1920s, the male Board of Directors seized control of the hospital, and relegated women to auxiliary roles. CONCLUSIONS: Health and social issues of the United States at the turn of the century are still problematic as a new century approaches and pertain to maternal-child health, foster care, and immigration. Feminists, including nurses, have played a central role in creating solutions. Knowledge of some of their incredible effort has been lost, particularly nursing's history in the western United States.

Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man.

1. Following intravenous administration to animals at 2.5 mg/kg, darifenacin exhibited terminal plasma half-lifes < 2 h due to high plasma clearance (with respect to blood flow) and volumes of distribution greater than total body water. 2. Following oral administration to animals at doses > 4 mg/kg there was evidence of saturation of clearance since oral AUCs exceeded those expected from the high plasma clearances. In addition, terminal plasma half-lifes were greater than those estimated from intravenous administration. 3. In man, oral clearance was high with respect to liver blood flow. 4. Following oral administration of the radiolabelled drug to animals and man, unchanged darifenacin was only a minor component of the faecal radioactivity indicating that darifenacin was well absorbed from the gut. 5. Darifenacin was metabolized by three main routes in all species: monohydroxylation, oxidative dihydrobenzfuran ring opening and N-dealkylation. There were no marked species differences in the metabolism of darifenacin.

Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans.

BACKGROUND: The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects. METHODS AND RESULTS: Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QTmax and QTmin were calculated similarly, and QT-interval dispersion was measured as QTmax-QTmin at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 +/- 8.7% at a heart rate of 60 bpm (P < .01) and by 7.4 +/- 8.2% at a heart rate of 150 bpm (P < .05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate. CONCLUSIONS: Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.

Prevalence of exercise-induced asthma in schoolchildren in Kingston, St. Andrew and St. Catherine, Jamaica.

A cross-sectional study was done, focusing on the prevalence of exercise-induced asthma in Jamaica and variables that may account for this rate. No previous study of this nature had been undertaken, and the investigators contend that there is a need to identify children who suffer from this condition but are unaware of it. A sample of 214 students from primary and secondary schools in the Corporate Area were chosen and given questionnaires to complete. Eighty-four of the children reported a history consistent with that of exercise-induced asthma and were further subjected to stress testing for a definitive diagnosis of this condition. A prevalence of 20.8% [C.I. +/- 5.35] was identified which reflected a rate comparable to that recorded in North America. There was a significantly higher prevalence in children of primary school ages, but all other variables considered for significance testing to determine associations between these and the prevalence of EIA proved not significant. A recommendation has been made for opportunity screening by medical practitioners.

Prevalence of exercise-induced asthma in schoolchildren in Kingston, St. Andrew and St. Catherine, Jamaica

A cross-sectional study was done, focusing on the prevalence of exercise-induced asthma in Jamaica and variables that may account for this rate. No previous study of this nature had been undertaken, and the investigators contend that there is a need to identify children who suffer from this condition but are unaware of it. A sample of 214 students from primary and secondary schools in the corporate area were chosen and given questionnaires to complete. Eighty-four of the children reported a history consistent with that of exercise-induced asthma and were further subjected to stress testing for a definitive diagnosis of this condition. A prevalence of 20.8 per cent [C.I ñ 5.35] was identified which reflected a rate comparable to that recorded in North America. There was a significantly higher prevalence in children of primary school ages, but all other variables considered for significance testing to determine associations between these and the prevalence of EIA proved not significant. A recomendation has been made for opportunity screening by medical practitioners

A survey of knowledge of family planning (FP) methods among Kenyan medical doctors: secondary data analysis.

PIP: This survey, conducted between October 1989 and March 1990, to determine the knowledge, attitude, practice, and provision of family planning of a sample of 376 Kenyan medical doctors, reports on the aspects of knowledge of family planning (FP) methods. Kenyan medical doctors had low-to-average knowledge of the association between oral contraceptives (OCs) and the risk of various medical conditions and the mechanism of action of steroidal contraceptives. Their knowledge of the effectiveness of various program methods was average to high. There was a linear relationship between monthly income and knowledge of effectiveness of OCs, according to which physicians earning more had less knowledge than their colleagues who earned less (Z = 2.318, p = 0.02). A stepwise unconditional logistic regression model showed that two variables, department where most work is performed and sex, are significantly associated with better knowledge. Use of these operational variables for assessing medical doctors' knowledge of FP methods gave a better resolution of the extent and perhaps the quality of counseling and advice they provided to their FP clients. At the same time, the need for update courses in FP for medical doctors is unquestionable and long overdue.^ieng

A survey of attitude of Kenyan medical doctors on family planning (FP): secondary data analysis.

PIP: This was part of a survey conducted between November 1989 and March 1990 to determine the knowledge, attitude, practice, and provision of family planning (FP) by a sample of Kenyan medical doctors. This part of the survey reports on the attitude as assessed through several attitudinal variables. Medical doctors had an average-to-high (60-98%) positive attitude about the relationship between population/economic growth and the need for FP, the effectiveness of the FP campaign in Kenya, and the ideal family size being 0-4 children. However, the proportion of doctors who considered the ideal family size to be 0-2 children dropped to a mere 23%. In light of the 1993 Kenyan total fertility rate of 5.4, an ideal family size of 0-4 children would be a worthwhile ambition for Kenyans, the majority of whom are of low socioeconomic status. Important covariates were future fertility intentions (desire for children), doctors' place of work, and religion. It is very important that the FP campaign continue to promote small families in Kenya.^ieng

Perceptions and practices relating to condom use among urban men in Haiti.

This report is based on a survey conducted in 1986-87 of sexually active adult male residents in a low-income community of Port-au-Prince, Haiti. The objectives were to investigate knowledge of and attitudes toward condoms; to evaluate the effectiveness of the existing condom distribution program; and to obtain information that can be used in the design of strategies to increase condom acceptance and use among men throughout Haiti. A final sample of 706 sexually active adult male residents in stable unions, including a specially drawn sample of male partners of condom acceptors, were interviewed in their homes. Although condoms are almost universally known, they are rarely used. The majority felt that the responsibility for family planning should be borne by the woman. Whereas condoms may be of limited popularity for family planning purposes in Haiti, it should be determined whether they might be more acceptable as an effective means of controlling the spread of AIDS and other STDs.

PIP: Attitudes toward condom use and the effectiveness of a condom distribution program were investigated in a survey of 706 sexually active men residing in a low-income community in Port-au-prince, Haiti, in 1986-87. All respondents were in a stable sexual relationship at the time of the survey; 554 had received condoms (or their female partner had) from the Cite Soleil Family Planning Center, while the remaining respondents were recruited through a community sampling survey. The average age of study subjects was 33 years. 20% were married; the remaining men had been in a stable union for 8 years in the case of respondents recruited from the family planning center for 6 years in the case of men identified through the community survey. 25% of men in the former group and 15% of those in the latter group reported having had sexual relations with a person other than their regular partner in the 3 months preceding the interview. Although 99% of men in the community survey had heard of condoms, none had ever used this method; ever-use of any form of contraception was only 3% in this subsample. In contrast, 43% of men recruited from the family planning center had used condoms at some point and 5% were current users (contributing 13% of all current contraceptive use). 96% of ever-users of condoms reported that their female partner had obtained the method; however, only 10% states that their partner was influential in their decision to use condoms and only 2% agreed that the husband should take responsibility for pregnancy prevention. The low prevalence of condom use in this sample does not reflect opposition to family planning (93% supported the concept), concerns about efficacy (90% trusted the method), a perception that condoms are for casual sexual encounters (only 1% stated this opinion), or supply constraints. These findings indicate the need for an IEC campaign to promote more widespread condom use and male responsibility for family planning.

Pharmacokinetics of trospectomycin sulphate in healthy subjects after single intravenous and intramuscular doses.

The pharmacokinetics of trospectomycin (75-1000 mg free base equivalents) were studied in 128 healthy males (eight per dose group), after a 20 min intravenous (i.v.) infusion and intramuscular (i.m.) injection of trospectomycin sulphate. The concentrations of trospectomycin in serum were described by bi- or tri-exponential disposition functions indicating an initial half-life of 1.1-1.4 h for the i.v. dose and 1.6-2.1 h for the i.m. dose and terminal half-lives of over 15 h. Most of the drug was eliminated rapidly (mean residence time 5-12 h). The distribution volume was 59-112% of body weight and clearance was 112-152 ml min-1. The absorption into blood after i.m. dosing was rapid. The area under the concentration-time curve and maximum concentration values were linearly related to dose. Serum drug concentrations fell below the minimum inhibitory concentration values for a variety of organisms by 8-12 h, which indicates that two or three times daily dosing would be appropriate. However, the long terminal half-life suggests that significant accumulation is likely in some tissues with an 8 h dose interval and this may prolong the action of trospectomycin.