Clinical Investigation of Topical Antimicrobials in Healthy Volunteers

OBJECTIVE: To evaluate the antibacterial activity, onset of action, and duration of action of four topical antimicrobial gels containing cetrimide, bacitracin, polymyxin B sulfate, and a placebo gel. DESIGN: Multiples (1×, 2×, 4×, 8×) of minimally inhibitory in vitro drug concentrations were formulated in a gel vehicle. Antibacterial activity was evaluated using a scrub-wash methodology on artificially inoculated skin over an 8-hour study period. SETTING AND PARTICIPANTS: Healthy volunteers with intact forearm skin participated in the study. A standardized culture of Staphylococcus aureus NCTC 6571 was applied to four areas on each forearm, randomly assigned topical treatments were applied, and sites were sampled at predetermined time intervals using a surfactant wash fluid. OUTCOME MEASURES: Recovered bacteria were quantitated, allowing a comparison of antibacterial activity. RESULTS: Two-way and one-way ANOVA and a Scheffe test confirmed significant differences in antibacterial effect between the formulations containing 4 and 8 times the minimally inhibitory in vitro concentrations and placebo (p < 0.05). Duration of action was similar for all preparations; however, onset appeared to be faster with the formulations containing 4 and 8 times minimally inhibitory in vitro concentrations. CONCLUSIONS: The two topical preparations containing 4 and 8 times the minimally inhibitory in vitro concentrations of cetrimide, bacitracin, and polymyxin B sulfate demonstrated significant antibacterial activity and may have potential for further clinical investigations.

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Pharmacological Evaluation of Ticlopidine, A Novel Inhibitor of Platelet Function

10.1055/s-0039-1680487 ◽

1977 ◽

Author(s):

M. Johnson ◽

P. L. Walton ◽

R. C. Cotton ◽

C. J. L. Strachau

Keyword(s):

Survival Time ◽

Platelet Function ◽

Thrombus Formation ◽

Antiplatelet Agent ◽

Dose Effect ◽

Onset Of Action ◽

Duration Of Action ◽

Platelet Survival ◽

Induced Aggregation

Ticlopidine (T), 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno(3,2-C)pyridine hydrochloride (a product of Parcor Research) has been evaluated as an antiplatelet agent in various animal species and in human volunteers. T was inactive in vitro, but inhibited platelet aggregation induced by ADP, collagen, thrombin, arachidonic acid and prostaglandin (PG) endoperoxide, when administered orally to mice, rats, rabbits, guinea pigs, pigs, dogs and baboons. Platelet adhesiveness was reduced but platelet survival time was normal in treated animals. Basal PG synthesis and platelet ultra-structure were unaffected by T.T protected against acute thrombocytopenia and death from pulmonary embolism induced by i. v. injection of ADP or collagen. Thrombus formation in experimental models of extra-corporeal circulation and deep venous thrombosis was also impaired.In man, a single oral dose of 500mg was shown to be a potent inhibitor of ADP, collagen, adrenaline, ristocetin, bovine fibrinogen and 5HT-induced aggregation. A dose-effect relationship was apparent, 250 and 500mg resulting in ~47 and 75% inhibition of ADP-induced aggregation respectively. Inhibition was sustained by chronic daily dosing.There was a delay in the onset of action of T in vivo, but which then persisted after withdrawal for at least 48 hours, with no evidence of rebound hyperactivity. The duration of action of T correlated with platelet survival time, suggesting an irreversible modification of platelet function. T is a potent platelet inhibitor, exhibiting a novel mode of action and lack of agonist specificity, which may be of value in the treatment of thrombotic conditions.

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Activity of Potential Alternative Treatment Agents for Stenotrophomonas maltophilia Isolates Nonsusceptible to Levofloxacin and/or Trimethoprim-Sulfamethoxazole

Journal of Clinical Microbiology ◽

10.1128/jcm.01603-19 ◽

2019 ◽

Vol 58 (2) ◽

Cited By ~ 3

Author(s):

M. Biagi ◽

X. Tan ◽

T. Wu ◽

M. Jurkovic ◽

A. Vialichka ◽

...

Keyword(s):

Stenotrophomonas Maltophilia ◽

Clinical Investigation ◽

Infection Type ◽

Geographic Origin ◽

Drug Effects ◽

Polymyxin B ◽

Surveillance Program ◽

Content Type ◽

Antimicrobial Surveillance

ABSTRACT Stenotrophomonas maltophilia is difficult to treat due to the production of multiple intrinsic and acquired mechanisms of resistance. Trimethoprim-sulfamethoxazole (TMP-SMZ) and the fluoroquinolones have traditionally been considered the drugs of choice but are plagued by increasing resistance and adverse drug effects. The objective of this study was to evaluate the in vitro activities of 12 clinically relevant antimicrobials against clinical S. maltophilia isolates nonsusceptible to levofloxacin and/or TMP-SMZ. A diverse panel of 41 clinical S. maltophilia isolates collected through the SENTRY Antimicrobial Surveillance Program from 2008 to 2018 was evaluated against ceftazidime, ceftazidime-avibactam, chloramphenicol, delafloxacin, levofloxacin, moxifloxacin, eravacycline, minocycline, omadacycline, polymyxin B, and tigecycline. MICs were determined in triplicate via reference broth microdilution and interpreted according to CLSI guidelines where available. MIC distributions and susceptibilities were also compared across infection type, acquisition setting, and geographic origin. Susceptibilities to levofloxacin and TMP-SMZ were 29.3% and 36.6%, respectively. Minocycline displayed the highest susceptibility rate overall (92.7%) and the lowest MIC90 value (4 mg/liter) of any of the 12 agents tested. Only 3 isolates were resistant to levofloxacin, TMP-SMZ, and minocycline. Polymyxin B and tigecycline were the second most active agents. No significant differences were observed in MIC distributions across the 3 strata evaluated. These data demonstrate that few antimicrobials, old or new, maintain reliable activity against resistant S. maltophilia. The role of minocycline in the treatment of infections due to S. maltophilia warrants further clinical investigation given its potent in vitro activity and favorable adverse effect profile.

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Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue

Thrombosis and Haemostasis ◽

10.1160/th10-05-0287 ◽

2011 ◽

Vol 105 (02) ◽

pp. 302-312 ◽

Cited By ~ 21

Author(s):

Thijs van Iersel ◽

Heimo Stroissnig ◽

Peter Giesen ◽

Johan Wemer ◽

Karin Wilhelm-Ogunbiyi

Keyword(s):

Healthy Volunteers ◽

Clinical Investigation ◽

Dose Range ◽

Plasma Concentrations ◽

Human Study ◽

Bleeding Risk ◽

High Dose ◽

Multiple Dosing ◽

Relevant Dose

SummarySolulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6–30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15–30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.

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Assessment of Differential Blockade by Amitriptyline and Its N -Methyl Derivative in Different Species by Different Routes

Anesthesiology ◽

10.1097/00000542-200306000-00028 ◽

2003 ◽

Vol 98 (6) ◽

pp. 1484-1490 ◽

Cited By ~ 39

Author(s):

Peter Gerner ◽

Anna E. Haderer ◽

Mustafa Mujtaba ◽

Yukari Sudoh ◽

Sanjeet Narang ◽

...

Keyword(s):

Sciatic Nerve ◽

Nerve Fibers ◽

Spinal Block ◽

Na Channel ◽

Channel Blockers ◽

Patch Clamp Technique ◽

Duration Of Action ◽

Drug Concentrations ◽

Nerve Model

Background Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. Methods The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). Results In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. Conclusions Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.

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Distribution and Antimicrobial Activity of Ciprofloxacin in Human Soft Tissues

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1307 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1307-1309 ◽

Cited By ~ 49

Author(s):

Martin Brunner ◽

Ursula Hollenstein ◽

Simon Delacher ◽

Dorothea Jäger ◽

Rainer Schmid ◽

...

Keyword(s):

Antimicrobial Activity ◽

Serum Concentration ◽

Healthy Volunteers ◽

Intravenous Administration ◽

Soft Tissues ◽

Total Serum ◽

Drug Concentrations ◽

Simulation Based ◽

In Vitro Simulation

ABSTRACT Interstitial ciprofloxacin concentrations in soft tissues were measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum drug concentrations; the interstitium-to-serum concentration ratios ranged from 0.55 to 0.73. An in vitro simulation based on interstitial pharmacokinetics showed a substantially lower antimicrobial activity than did the simulation based on serum pharmacokinetics. Thus, ciprofloxacin concentrations at the site of effect may be subinhibitory although effective concentrations are attained in serum.

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In Vitro Antibacterial Activity of Curcumin–Polymyxin B Combinations against Multidrug-Resistant Bacteria Associated with Traumatic Wound Infections

Journal of Natural Products ◽

10.1021/acs.jnatprod.6b00286 ◽

2016 ◽

Vol 79 (6) ◽

pp. 1702-1706 ◽

Cited By ~ 27

Author(s):

Jonathan W. Betts ◽

Amir S. Sharili ◽

Roberto M. La Ragione ◽

David W. Wareham

Keyword(s):

Antibacterial Activity ◽

Polymyxin B ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Wound Infections ◽

Multidrug Resistant Bacteria ◽

In Vitro Antibacterial Activity ◽

Traumatic Wound

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Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01337-20 ◽

2020 ◽

Vol 64 (12) ◽

Author(s):

Jitender Yadav ◽

Sana Ismaeel ◽

Ayub Qadri

Keyword(s):

Antibacterial Activity ◽

Polymyxin B ◽

Resistant Bacteria ◽

Bacterial Membrane ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Antibiotic Resistant ◽

Gram Negative ◽

Drug Resistant Bacteria

ABSTRACT Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of Salmonella and at least two other Gram-negative bacteria in vitro. This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.

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Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01474-16 ◽

2016 ◽

pp. AAC.01474-16 ◽

Cited By ~ 27

Author(s):

Manuel Tsiang ◽

Gregg S. Jones ◽

Joshua Goldsmith ◽

Andrew Mulato ◽

Derek Hansen ◽

...

Keyword(s):

Antiviral Activity ◽

Clinical Investigation ◽

Cross Resistance ◽

Strand Transfer ◽

Resistance Profile ◽

Drug Concentrations ◽

Treatment Naïve ◽

T Cell Lines ◽

Hiv 1

Bictegravir (BIC; GS-9883), a novel potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN) specifically targets IN strand transfer activity (IC50= 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selectivein vitroantiretroviral activity in both T-cell lines and primary human T-lymphocytes with EC50values ranging from 1.5 to 2.4 nM and selectivity indices up to 8800 relative to cytotoxicity. BIC exhibits synergisticin vitroantiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed anin vitroresistance profile markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with high-level INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC compared to DTG. In dose-escalation experiments conductedin vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, respectively. A recombinant virus with the BIC-selected dual mutations M50I+R263K in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to WT virus (2.8-fold). All BIC-selected variants exhibited low to intermediate level cross-resistance to RAL, DTG, and EVG (<8-fold), but remained susceptible to other classes of antiretrovirals. A high barrier toin vitroresistance emergence for both BIC and DTG was also observed in viral breakthrough studies in the presence of constant clinically relevant drug concentrations. The overall virologic profile of BIC supports its ongoing clinical investigation in combination with other antiretroviral agents for both treatment-naïve and experienced HIV-infected patients.

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