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Background: In the United States, e-cigarettes, or vapes, are the second most commonly used tobacco product. Despite abundant smartphone app-based cigarette cessation programs, there are few such programs for vaping and even fewer supporting data., Objective: This exploratory, prospective, single-arm, remote cohort study of the Pivot vaping cessation program assessed enrollment and questionnaire completion rates, participant engagement and retention, changes in attitudes toward quitting vaping, changes in vaping behavior, and participant feedback. We aimed to establish early data to inform program improvements and future study design., Methods: American adults aged ≥21 years who vaped daily, reported ≥5 vape sessions per day, and planned to quit vaping within 6 months were recruited on the web. Data were self-reported via app- and web-based questionnaires. Outcomes included engagement and retention (ie, weeks in the program, number of Pivot app openings, and number of messages sent to the coach), vaping attitudes (ie, success in quitting and difficulty staying quit), vaping behavior (ie, quit attempts, Penn State Electronic Cigarette Dependence Index, 7- and 30-day point-prevalence abstinence [PPA], and continuous abstinence [defined as ≥7-day PPA at 12 weeks+30-day PPA at 26 weeks+0 vaping sessions since 12 weeks]), and participant feedback., Results: In total, 73 participants onboarded (intention-to-treat sample); 68 (93%) completed the 12- and 26-week questionnaires (completer samples). On average, participants were active in Pivot for 13.8 (SD 7.3) weeks, had 87.3 (SD 99.9) app sessions, and sent 37.6 (SD 42.3) messages to their coach over 26 weeks. Mean success in quitting and difficulty staying quit (scale of 1-10) improved from baseline to 12 weeks-4.9 (SD 2.9) to 7.0 (SD 3.0) and 4.0 (SD 2.8) to 6.2 (SD 3.1), respectively (P<.001 in both cases). Most participants (64/73, 88%) made ≥1 quit attempt. At 26 weeks, intention-to-treat 7-day PPA, 30-day PPA, and continuous abstinence rates were 48% (35/73), 45% (33/73), and 30% (22/73), respectively. In total, 45% (33/73) of the participants did not achieve 7-day PPA at 26 weeks; their mean Penn State Electronic Cigarette Dependence Index score decreased from baseline (13.9, SD 3.1) to 26 weeks (10.8, SD 4.5; mean change -3.2, SD 3.9; P<.001); 48% (16/33) of these participants improved in the e-cigarette dependence category. At 2 weeks, 72% (51/71) of respondents reported that using Pivot increased their motivation to quit vaping; at 4 weeks, 79% (55/70) reported using Pivot decreased the amount they vaped per day., Conclusions: In this first evaluation of Pivot in adult daily vapers, questionnaire completion rates were >90%, average program engagement duration was approximately 14 weeks, and most participants reported increased motivation to quit vaping. These and early cessation outcomes herein suggest a role for Pivot in vaping cessation and will inform associated future study and program improvements., (©Jennifer D Marler, Craig A Fujii, MacKenzie T Utley, Daniel J Balbierz, Joseph A Galanko, David S Utley. Originally published in JMIR Formative Research (https://formative.jmir.org), 28.10.2024.)

Background: Increased smartphone ownership has led to the development of mobile smoking cessation programs. Although the related body of evidence, gathered through the conduct of randomized controlled trials (RCTs), has grown in quality and rigor, there is a need for longer-term data to assess associated smoking cessation durability., Objective: The primary aim was to compare smoking cessation outcomes at 52 weeks in adult smokers randomized to a mobile smoking cessation program, Pivot (intervention), versus QuitGuide (control). The secondary aims included comparison of other smoking-related behaviors, outcomes and participant feedback, and exploratory analyses of baseline factors associated with smoking cessation., Methods: In this remote pilot RCT, cigarette smokers in the United States were recruited on the web. Participants were offered 12 weeks of free nicotine replacement therapy (NRT). Data were self-reported via a web-based questionnaire with videoconference biovalidation in participants who reported 7-day point-prevalence abstinence (PPA). Outcomes focused on cessation rates with additional assessment of quit attempts, cigarettes per day (CPD), self-efficacy via the Smoking Abstinence Self-Efficacy Questionnaire, NRT use, and participant feedback. Cessation outcomes included self-reported 7- and 30-day PPA, abstinence from all tobacco products, and continuous abstinence. PPA and continuous abstinence were biovalidated using witnessed breath carbon monoxide samples. Exploratory post hoc regression analyses were performed to identify baseline variables associated with smoking cessation., Results: Participants comprised 188 smokers (n=94, 50% in the Pivot group and n=94, 50% in the QuitGuide group; mean age 46.4, SD 9.2 years; n=104, 55.3% women; n=128, 68.1% White individuals; mean CPD 17.6, SD 9.0). Several cessation rates were higher in the Pivot group (intention to treat): self-reported continuous abstinence was 20% (19/94) versus 9% (8/94; P=.03) for QuitGuide, biochemically confirmed abstinence was 31% (29/94) versus 18% (17/94; P=.04) for QuitGuide, and biochemically confirmed continuous abstinence was 19% (18/94) versus 9% (8/94; P=.046) for QuitGuide. More Pivot participants (93/94, 99% vs 80/94, 85% in the QuitGuide group; P<.001) placed NRT orders (mean 3.3, SD 2.0 vs 1.8, SD 1.6 for QuitGuide; P<.001). Pivot participants had increased self-efficacy via the Smoking Abstinence Self-Efficacy Questionnaire (mean point increase 3.2, SD 7.8, P<.001 vs 1.0, SD 8.5, P=.26 for QuitGuide). QuitGuide participants made more mean quit attempts (7.0, SD 6.3 for Pivot vs 9.5, SD 7.5 for QuitGuide; P=.01). Among those who did not achieve abstinence, QuitGuide participants reported greater CPD reduction (mean -34.6%, SD 35.5% for Pivot vs -46.1%, SD 32.3% for QuitGuide; P=.04). Among those who reported abstinence, 90% (35/39) of Pivot participants and 90% (26/29) of QuitGuide participants indicated that their cessation program helped them quit., Conclusions: This pilot RCT supports the long-term effectiveness of the Pivot mobile smoking cessation program, with abstinence rates durable to 52 weeks., Trial Registration: ClinicalTrials.gov NCT04955639; https://clinicaltrials.gov/ct2/show/NCT04955639., (©Jennifer D Marler, Craig A Fujii, MacKenzie T Utley, Daniel J Balbierz, Joseph A Galanko, David S Utley. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 18.09.2023.)

Background: Cigarette smoking remains the leading cause of preventable illness and death, underscoring ongoing need for evidence-based solutions. Pivot, a US Clinical Practice Guideline-based mobile smoking cessation program, comprises a personal carbon monoxide breath sensor; a smartphone app; in-app, text-based human-provided coaching; nicotine replacement therapy; and a moderated web-based community. Promising Pivot cohort studies have established the foundation for comparative assessment., Objective: This study aimed to compare engagement, retention, attitudes toward quitting smoking, smoking behavior, and participant feedback between Pivot and QuitGuide, a US Clinical Practice Guideline-based smoking cessation smartphone app from the National Cancer Institute., Methods: In this remote pilot randomized controlled trial, cigarette smokers in the United States were recruited on the web and randomized to Pivot or QuitGuide. Participants were offered 12 weeks of free nicotine replacement therapy. Data were self-reported via weekly web-based questionnaires for 12 weeks and at 26 weeks. Outcomes included engagement and retention, attitudes toward quitting smoking, smoking behavior, and participant feedback. The primary outcome was self-reported app openings at 12 weeks. Cessation outcomes included self-reported 7- and 30-day point prevalence abstinence (PPA), abstinence from all tobacco products, and continuous abstinence at 12 and 26 weeks. PPA and continuous abstinence were biovalidated via breath carbon monoxide samples., Results: Participants comprised 188 smokers (94 Pivot and 94 QuitGuide): mean age 46.4 (SD 9.2) years, 104 (55.3%) women, 128 (68.1%) White individuals, and mean cigarettes per day 17.6 (SD 9.0). Engagement via mean "total app openings through 12 weeks" (primary outcome) was Pivot, 157.9 (SD 210.6) versus QuitGuide, 86.5 (SD 66.3; P<.001). Self-reported 7-day PPA at 12 and 26 weeks was Pivot, 35% (33/94) versus QuitGuide, 28% (26/94; intention to treat [ITT]: P=.28) and Pivot, 36% (34/94) versus QuitGuide, 27% (25/94; ITT: P=.12), respectively. Self-reported 30-day PPA at 12 and 26 weeks was Pivot, 29% (27/94) versus QuitGuide, 22% (21/94; ITT: P=.32) and Pivot, 32% (30/94) versus QuitGuide, 22% (21/94; ITT: P=.12), respectively. The biovalidated abstinence rate at 12 weeks was Pivot, 29% (27/94) versus QuitGuide, 13% (12/94; ITT: P=.008). Biovalidated continuous abstinence at 26 weeks was Pivot, 21% (20/94) versus QuitGuide, 10% (9/94; ITT: P=.03). Participant feedback, including ease of setup, impact on smoking, and likelihood of program recommendation were favorable for Pivot., Conclusions: In this randomized controlled trial comparing the app-based smoking cessation programs Pivot and QuitGuide, Pivot participants had higher engagement and biovalidated cessation rates and more favorable user feedback at 12 and 26 weeks. These findings support Pivot as an effective, durable mobile smoking cessation program., Trial Registration: ClinicalTrials.gov NCT04955639; https://clinicaltrials.gov/ct2/show/NCT04955639., (©Jennifer D Marler, Craig A Fujii, MacKenzie T Utley, Daniel J Balbierz, Joseph A Galanko, David S Utley. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 24.11.2022.)

Background: Despite decreasing prevalence over the last several decades, cigarette smoking remains the leading cause of preventable death and disease, underscoring the need for innovative, effective solutions. Pivot is a novel, inclusive smoking cessation program designed for smokers along the entire spectrum of readiness to quit. Pivot leverages proven methods and technological advancements, including a personal portable breath carbon monoxide sensor, smartphone app, and in-app text-based coaching. We previously reported outcomes from the end of active Pivot program participation in 319 adult smokers. Herein, we report longer-term follow up in this cohort., Objective: The aim of this study was to assess and report participant outcomes 3 months after completion of Pivot, including smoking behavior, quit rates, continuous abstinence rates and durability, and predictors of abstinence., Methods: This prospective remote cohort study included US-based cigarette smokers aged 18 to 65 years who smoked ≥5 cigarettes per day (CPD). Three months after completion of active participation in Pivot, final follow-up data were collected via an online questionnaire. Outcomes included smoking behavior (CPD and quit attempts), self-reported quit rates (7- and 30-day point prevalence abstinence [PPA]), and continuous abstinence rates (proportion who achieved uninterrupted abstinence) and duration. Exploratory regression analyses were performed to identify baseline characteristics associated with achievement of 7-day PPA, 30-day PPA, and continuous abstinence., Results: A total of 319 participants completed onboarding (intention-to-treat [ITT]); 288/319 participants (90.3%) completed follow up (completers) at a mean of 7.2 (SD 1.2) months after onboarding. At final follow up, CPD were reduced by 52.6% (SE 2.1; P<.001) among all 319 participants, and most completers (152/288, 52.8%) reduced their CPD by at least 50%. Overall, most completers (232/288, 80.6%) made at least one quit attempt. Quit rates increased after the end of Pivot; using ITT analyses, 35.4% (113/319) achieved 7-day PPA and 31.3% (100/319) achieved 30-day PPA at final follow up compared with 32.0% (102/319) and 27.6% (88/319), respectively, at the end of the Pivot program. Continuous abstinence was achieved in about a quarter of those who onboarded (76/319, 23.8%) and in most who reported 30-day PPA at the end of Pivot (76/88, 86.4%), with a mean abstinence duration of 5.8 (SD 0.6) months. In exploratory regression analyses, lower baseline CPD, more positive baseline attitudes reflecting higher self-efficacy (higher confidence to quit and lower perceived difficulty of quitting), and higher education were associated with achieving abstinence., Conclusions: This study provides the first longer-term outcomes of the Pivot smoking cessation program. At final follow up, quit rates increased and continuous abstinence was favorable; the majority who achieved abstinence at the end of Pivot sustained abstinence throughout follow up. Decreases in CPD persisted and most participants made a quit attempt. Overall, final follow-up outcomes were stable or improved when compared to previous outcomes from the end of the program. These findings validate earlier results, and suggest that Pivot is an effective and durable solution for smoking cessation., Trial Registration: ClinicalTrials.gov NCT03295643; https://clinicaltrials.gov/ct2/show/NCT03295643., (©Jennifer D Marler, Craig A Fujii, Joseph A Galanko, Daniel J Balbierz, David S Utley. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 15.02.2021.)

Background: Tobacco use is the leading cause of preventable morbidity and mortality. Existing evidence-based treatments are underutilized and have seen little recent innovation. The success of personal biofeedback interventions in other disease states portends a similar opportunity in smoking cessation. The Pivot Breath Sensor is a personal interactive FDA-cleared (over-the-counter) device that measures carbon monoxide (CO) in exhaled breath, enabling users to link their smoking behavior and CO values, and track their progress in reducing or quitting smoking., Objective: The objective of this study is to assess the Pivot Breath Sensor in people who smoke cigarettes, evaluating changes in attitudes toward quitting smoking, changes in smoking behavior, and use experience., Methods: US adults (18-80 years of age, ≥10 cigarettes per day [CPD]) were recruited online for this remote 12-week study. Participants completed a screening call, informed consent, and baseline questionnaire, and then were mailed their sensor. Participants were asked to submit 4 or more breath samples per day and complete questionnaires at 1-4, 8, and 12 weeks. Outcomes included attitudes toward quitting smoking (Stage of Change, success to quit, and perceived difficulty of quitting), smoking behavior (quit attempts, CPD reduction, and 7-, 30-day point prevalence abstinence [PPA]), and use experience (impact and learning)., Results: Participants comprised 234 smokers, mean age 39.9 (SD 11.3) years, 52.6% (123/234) female, mean CPD 20.3 (SD 8.0). The 4- and 12-week questionnaires were completed by 92.3% (216/234) and 91.9% (215/234) of participants, respectively. Concerning attitude outcomes, at baseline, 15.4% (36/234) were seriously thinking of quitting in the next 30 days, increasing to 38.9% (84/216) at 4 weeks and 47.9% (103/215) at 12 weeks (both P<.001). At 12 weeks, motivation to quit was increased in 39.1% (84/215), unchanged in 54.9% (118/215), and decreased in 6.0% (13/215; P<.001). Additional attitudes toward quitting improved from baseline to 12 weeks: success to quit 3.3 versus 5.0 (P<.001) and difficulty of quitting 2.8 versus 4.3 (P<.001). Regarding smoking behavior, at 4 weeks, 28.2% (66/234) had made 1 or more quit attempts (≥1 day of abstinence), increasing to 48.3% (113/234) at 12 weeks. At 4 weeks, 23.1% (54/234) had reduced CPD by 50% or more, increasing to 38.5% (90/234) at 12 weeks. At 12 weeks, CPD decreased by 41.1% from baseline (P<.001), and 7- and 30-day PPA were 12.0% (28/234) and 6.0% (14/234), respectively. Concerning use experience, 75.3% (171/227) reported the sensor increased their motivation to quit. More than 90% (>196/214) indicated the sensor taught them about their CO levels and smoking behavior, and 73.1% (166/227) reported that seeing their CO values made them want to quit smoking., Conclusions: Use of the Pivot Breath Sensor resulted in a significant increase in motivation to quit, a reduction in CPD, and favorable quit attempt rates. These outcomes confer increased likelihood of quitting smoking. Accordingly, the results support a role for biofeedback via personal CO breath sampling in smoking cessation., Trial Registration: ClinicalTrials.gov NCT04133064; https://clinicaltrials.gov/ct2/show/NCT04133064., (©Jennifer D Marler, Craig A Fujii, Kristine S Wong, Joseph A Galanko, Daniel J Balbierz, David S Utley. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 02.10.2020.)

Background: Cigarette smoking is the leading cause of preventable morbidity and mortality, excess health care expenditure, and lost work productivity. Otherwise effective evidence-based treatments have had limited success owing to challenges with access, engagement, and scale. Pivot is a comprehensive digital smoking cessation program that incorporates a Food and Drug Administration-cleared carbon monoxide breath sensor, smartphone app, and text-based human coaching., Objective: This initial evaluation of Pivot aimed to assess participant engagement, changes in attitudes toward quitting, and changes in smoking behavior., Methods: US cigarette smokers aged 18 to 65 years who smoked ≥5 cigarettes per day (CPD) were recruited online. Participants completed a screening call, electronic informed consent, registration, and onboarding before beginning Pivot. Pivot includes 5 sequential stages (Explore, Build, Mobilize, Quit, and Secure), taking 14.5 to 18.5 weeks to complete. Data were collected via app and online questionnaires. Outcomes included engagement and retention (ie, weeks of active engagement and Pivot stage progression); attitudes toward quitting (ie, quit readiness, quit confidence, and expected difficulty maintaining quit); and smoking behavior (ie, quit attempts, cigarette reduction, and abstinence (7- and 30-day point prevalence abstinence [PPA])., Results: A total of 319 participants completed onboarding (intention-to-treat [ITT] sample); 272/319 participants (85.3%) completed the end-of-Pivot questionnaire (study completer sample). Most (212/319, 66.5%) were not ready to quit in the next 30 days at baseline. On average, participants actively engaged in the program for a mean 12.4 (SD 7.1) weeks. Pivot stage completion rates were Explore: 88.7% (283/319), Build: 57.4% (183/319), Mobilize: 43.6% (139/319), Quit: 41.1% (131/319), and Secure: 39.5% (126/319). Repeated measures linear mixed model analyses demonstrated positive changes in attitudes from baseline to Mobilize (pre-Quit): increased confidence to quit (4.2 to 7.4, P<.001) and decreased expected difficulty maintaining quit (3.1 to 6.8, P<.001). The quit attempt rate (ie, those making ≥1 quit attempt lasting ≥1 day) was 79.4% (216/272, completer). At the end of Pivot, 7-day PPA rates were 32.0% (102/319, ITT) and 37.5% (102/272, completer); 30-day PPA rates were 27.6% (88/319, ITT) and 32.4% (88/272, completer). Moreover, 30-day PPA rates were comparable among those ready and not ready to quit in the next 30 days at baseline. Of those not achieving abstinence, 25.9% (44/170, completer) achieved ≥50% reduction in CPD by study end., Conclusions: This study evaluated Pivot's initial performance with comparable quit rates among those ready and not ready to quit in the next 30 days at entry. The present data, considered with the program's accessibility, innovation, evidence-based foundation, and design for all smokers, suggest Pivot has the potential to address limitations of reach and scale and thereby advance smoking cessation efforts., Trial Registration: ClinicalTrials.gov NCT03295643; https://clinicaltrials.gov/ct2/show/NCT03295643 (Archived by WebCite at http://www.webcitation.org/75TiNe6BE)., (©Jennifer D Marler, Craig A Fujii, David S Utley, Lydia J Tesfamariam, Joseph A Galanko, Heather Patrick. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 04.02.2019.)

Background: Cigarette smoking remains the leading cause of preventable death and disease worldwide. Evidence-based approaches are available, but few people access them. Although digital solutions offer great promise for population reach, few multicomponent programs exist. Pivot is a comprehensive digital solution combining a Food and Drug Administration-cleared carbon monoxide (CO) breath sensor; cigarette logging; a 6-phase, app-delivered smoking cessation program based on the US Clinical Practice Guidelines; and dedicated human coaching via text-based chat., Objective: The purpose of this study was to assess program engagement, changes in attitudes toward smoking, self-reported changes in smoking behavior, and program acceptability for the initial phase of Pivot: Explore., Methods: A total of 48 participants enrolled, and 41 completed the study. About half the participants (54%, 22/41) were men, and the mean age was 43 years. Most (85%, 35/41) were daily smokers and smoked an average of 12 cigarettes per day. Explore includes CO breath sensing, logging cigarettes in-app, learning via in-app activities, and dedicated human coaching through a text messaging interface. Participants completed surveys at baseline and exit assessing attitudes toward quitting including readiness, perceived difficulty, and confidence in quit success. At exit, participants also completed a survey of changes in smoking behavior and ratings of program acceptability., Results: More than 80% of participants (34-39 of 41) took ≥1 CO breath sample each day, and more than 55% (23-27 of 41) took ≥5 samples each day. More than 65% of participants (27-34 of 41) logged ≥1 cigarette using the in-app logging feature each day. All 9 in-app activities had completion rates ≥80% (33-40 of 41). Response to coach-initiated outreach was also high, with all contacts receiving ≥73% (30-39 of 41) response. In matched pair analyses, significant positive changes in mean attitudes toward quitting (scale 1-10) were evident from baseline (T1) to study exit (T2), including increased readiness to quit (T1 mean=6.1, T2 mean=7.4, P=.005), lower perceived difficulty (T1 mean=3.7, T2 mean=5.6, P=.001), and greater expectations of success (T1 mean=4.5, T2 mean=6.5, P<.001). At exit, 78% (32/41) of participants reported decreasing the number of cigarettes smoked per day during the study. Participants rated program quality and satisfaction very high (mean ≥8 for all items)., Conclusions: These results support the feasibility and acceptability of the initial 9-day phase of Pivot: Explore. Participants had high levels of engagement with sensing, logging, learning, and coaching. Attitudes toward quitting improved significantly, and the majority of users indicated decreasing smoking behavior. Explore was designed to raise smoker awareness and motivation. Additional research is underway to assess how users progress through the full Pivot smoking cessation program and determine the program's effectiveness for achieving sustained cessation., (©Heather Patrick, Craig A Fujii, Debra B Glaser, David S Utley, Jennifer D Marler. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 18.12.2018.)

Although the microflora associated with oral mucositis initiated by cytotoxic therapy is not well characterized, several studies suggest that reduction of the microbial load in the oral cavity has some clinical benefit. The MICs of IB-367, a synthetic protegrin analog, ranged from 0.13 to 64 microgram/ml for gram-positive bacteria (Streptococcus mitis, Streptococcus sanguis, Streptococcus salivarius, and Staphylococcus aureus) and from 0.06 to 8 microgram/ml for gram-negative species (Klebsiella, Escherichia, and Pseudomonas). IB-367 exhibited rapid, microbicidal activity against both log- and stationary-phase cultures of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. At concentrations near the MICs for these two organisms (4 and 2 microgram/ml, respectively), IB-367 reduced viability by more than 3 logs in less than 16 min. Similarly, IB-367 effected a 4-log reduction of the endogenous microflora in pooled human saliva within 2 min at 250 microgram/ml, a concentration readily attained by local delivery. After nine serial transfers at 0.5x the MIC, the MIC of IB-367 for MRSA and P. aeruginosa increased only two to four times. In a phase I clinical study with healthy volunteers, IB-367 was well tolerated, with no detectable systemic absorption. One hour after treatment with 9 mg of IB-367, the prevalence of gram-negative bacteria and yeast was reduced, and the density of the predominant gram-positive oral flora was decreased 1,000 times. IB-367's properties (speed of killing, breadth of spectrum, and lack of resistance) make the compound a strong candidate for the prophylaxis of oral mucositis. Phase II clinical trials with IB-367 are under way for this indication in immunocompromised subjects.

Protegrin antimicrobial peptides possess activity against gram-positive and gram-negative bacteria and yeasts. An extensive structure-activity relationship (SAR) study was conducted on several hundred protegrin analogues to gain understanding of the relationship between the primary and secondary structure of the protegrins and their antimicrobial activities, and to identify a protegrin analogue for clinical development. Native sequence protegrins are cationic, amphiphilic peptides that are characterized by the presence of a beta-sheet structure that is maintained by two disulfide bridges. The presence of the beta-sheet is key to the stability of the protegrin structure; linearized analogues or analogues that have amino acid substitutions that eliminate hydrogen bonding across the beta-sheet have reduced activity, especially in the presence of physiological concentrations of NaCl. Also, maintaining amphiphilicity of the beta-sheet is key; analogues with substitutions of polar amino acids in the hydrophobic face have reduced activity. Analogues with reduced positive charge tend to be less active, an observation that is more marked for gram-negative than gram-positive bacteria, and may implicate binding to lipopolysaccharide as a key mechanistic step in the killing of gram-negative bacteria. A very large number of amino acid substitutions are tolerated by the protegrin structure, implying that overall structural features such as amphiphilicity, charge, and shape are more important to activity than the presence of specific amino acids. This lack of importance of specific stereochemistry is supported by the fact that completely D-amino acid substituted protegrins are fully potent. Based on the SAR studies, and on the microbiological data from an animal model, one protegrin analogue, IB-367, was selected for clinical development as a topical agent to prevent the oral mucositis associated with cancer therapy., (Copyright 2000 John Wiley & Sons, Inc.)

Protegrin-1 (PG-1) is a cysteine-rich, 18-residue beta-sheet peptide isolated from porcine leukocytes with antimicrobial activity against a broad range of microorganisms. The MICs of PG-1 against representative gram-positive and gram-negative bacteria ranged from 0.12 to 2 microg/ml. At these levels, PG-1 was rapidly bactericidal in vitro, reducing the number of viable CFU of either methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa by more than three log units in less than 15 min. Resistance to PG-1 did not develop after 11 subculturings of P. aeruginosa or 18 subcultures of MRSA in Mueller-Hinton broth containing PG-1 at one-half the MIC. Under similar conditions of serial passage, the MICs of norfloxacin and gentamicin against P. aeruginosa increased 10 and 190 times, respectively. Similarly, the MIC of norfloxacin against MRSA increased 85 times. Immunocompetent mice inoculated intraperitoneally (i.p.) with P. aeruginosa or S. aureus exhibited 93 to 100% mortality in the vehicle control group compared with 0 to 27% mortality in animals that received a single i.p. injection of PG-1 (0.5 mg/kg of body weight). Mice inoculated with S. aureus by intravenous (i.v.) injection and dosed 0 to 60 min later with a single i.v. injection of PG-1 (5 mg/kg) had a mortality of 7 to 33%, compared to a mortality of 73 to 93% in the vehicle controls. In leukopenic mice inoculated i.v. with vancomycin-resistant Enterococcus faecium, mortality was 87% in the vehicle control group and 33% in animals that received a single i.v. injection of PG-1 (2.5 mg/kg). Taken together, these data indicate that PG-1 has potential for use as an antimicrobial agent in the treatment of local or systemic infections caused by clinically relevant pathogens.