Reduced blood-brain barrier penetration of acne vulgaris antibiotic sarecycline compared to minocycline corresponds with lower lipophilicity

Introduction

Second-generation tetracycline-class antibiotics such as doxycycline and minocycline have been the mainstay treatment of moderate-to-severe acne vulgaris for over 50 years (1–3); however, the use of minocycline is often limited by vestibular side effects such as dizziness and tinnitus, leading to the inclusion of a warning for central nervous system side effects in the minocycline package insert (4). These side effects can impair an individual’s ability to perform daily tasks such as driving (4), thus contributing to the overall burden of managing acne vulgaris. In contrast, vestibular side effects are not typically associated with use of doxycycline (2). The higher lipophilicity of minocycline compared with doxycycline [e.g., distribution coefficient (logD) values of 1.11 (minocycline) vs. 0.95 (doxycycline) (5)] allows for greater penetration of the blood-brain barrier, thereby potentiating vestibular infiltration and by extension, dizziness and vertigo (2).

Sarecycline is a narrow-spectrum, 3rd generation tetracycline-class oral antibiotic approved by the US Food and Drug Administration (FDA) in 2018 for the treatment of moderate-to-severe acne vulgaris (6, 7). The efficacy and safety of sarecycline have been reported in two phase 3 randomized controlled trials [SC1401 (ClinicalTrials.gov identifier NCT02320149; N = 968) and SC1402 (ClinicalTrials.gov identifier NCT02322866); N = 1034], and its long-term safety was examined in a 40-week open-label extension study (ClinicalTrials.gov identifier NCT02413346; N = 490) (8, 9). Notably, low rates of vestibular-related adverse events (e.g., dizziness, motion sickness) were observed in these studies, and no events of vertigo or tinnitus were reported in patients receiving sarecycline (Figure 1). However, no clinical trials to date have compared sarecycline head-to-head with other tetracycline-class drugs (10), limiting the ability to make direct comparisons for safety and tolerability across therapies. Further, it remains unclear whether the biochemical properties of sarecycline (e.g., blood-brain barrier penetrance, lipophilicity) could be contributing to the low rates of vestibular adverse events in clinical trials.

FIGURE 1

Figure 1. Rates of vestibular-related adverse events in two phase 3 placebo-controlled clinical trials of sarecycline [SC1401 (N = 964) and SC1402 (N = 1026); representing the safety population] and a phase 3 open-label extension study (N = 483) (8, 9). In the open-label study, rates of adverse events were pooled for patients who received placebo in the phase 3 clinical trials and then received sarecycline (n = 236) and those who received sarecycline in the phase 3 clinical trials and continued receiving sarecycline in the open-label study (n = 247). Motion sickness was not reported in the open-label study. The number of patients who experienced these adverse events is shown in each bar.

Here, we investigated the potential relationship between the brain-penetrative and lipophilic attributes of sarecycline from 2 preclinical in vivo and in vitro analyses. In the first analysis, we examined the ability of sarecycline to penetrate the blood-brain barrier relative to minocycline in a rat model study. In the second analysis, we determined the lipophilicity of sarecycline compared with minocycline and doxycycline.

Materials and methods

Blood-brain barrier penetration study

Ethics statement

All protocols involving animals were approved by the Institutional Animal Care and Use Committee (IACUC).

Procedures

Six male Wistar rats (150–200 g; Charles River Laboratories, Wilmington, MA, USA) were used in this study. Each rat was pre-cannulated in the jugular vein. Rats were kept in individual cages, with water and feed ad libitum, and alternating 12 h light cycles. Before dosing, rats underwent an overnight fast (∼16 h) in metabolic cages and were weighed to determine dose volume (1.0 ml/kg). The rats were then intravenously (IV) dosed with either sarecycline (N = 3) or minocycline (N = 3) at a total dose of 1.0 mg/kg, and access to food was restored 2 h after dosing. Subsequently, rats were euthanized via CO₂ and brain samples and whole blood, collected via heart puncture, were harvested from 2 rats at each of the following time points: 1, 3, and 6 h postdosing.

Analysis

The endpoint of this analysis was concentration of sarecycline or minocycline in plasma (μg/ml) and in brain samples (μg/g) at 1, 3, and 6 h postdosing. Plasma and brain homogenate samples were prepared by protein precipitation with acetonitrile, followed by centrifugation. The samples were injected on an API 2000 mass spectrometer (Applied Biosystems, Foster City, CA, USA) and analyzed in positive ion mode using doxycycline as an internal standard. Values were calculated using Analyst 1.2 quantitation software (SciEx, Framingham, MA, USA). Linear through zero regression analysis with no weighting factor was used to determine the calculated concentrations of the injected samples.

Lipophilicity study

Procedure

Sarecycline, minocycline, and doxycycline were each prepared as 1.0 mg/ml stock solutions (4/8 ml) in 3 separate aqueous phase pH buffers (pH 3.5, 5.5, and 7.4). The pH of aqueous phase stock solutions was adjusted to within 0.1 of the desired pH before analysis; stock solutions had a further equilibration period of 2 h before pH adjustment as needed.

Aqueous phase stock solutions were quantified by high performance liquid chromatography (HPLC) before mixing with the organic phase to avoid any potential degradation effects. Next, 2 ml each of aqueous saturated octanol/chloroform and aqueous stock solution were combined and vortex-mixed to encourage interaction between phases. Each experimental condition was conducted in triplicate.

The mixtures were equilibrated at 25°C for 24 h at 750 rotations per minute to allow partitioning. At 2 intervals, the mixtures were vortex-mixed to ensure that an emulsion formed. Following equilibration, the mixtures were allowed to settle before aqueous and organic layers were separated into discrete HPLC vials.

Following 24-h equilibration and phase separation, final pH values of the aqueous phases were recorded. Sarecycline and doxycycline octanol and chloroform phases were diluted as needed with acetonitrile, and minocycline octanol and chloroform phases were diluted as needed with dimethyl sulfoxide. Phases were analyzed by HPLC.

Lipophilicity and data analysis

The endpoint of this analysis was the calculation of logD values for each compound at pH 3.5, 5.5, and 7.4. LogD values were calculated by the ratio of the peaks found in the aqueous phase vs. the organic layer, with lower values indicating less lipophilicity and higher values indicating greater lipophilicity. Confirmation of recovery was calculated by determining the concentration of the aqueous stock solution.

Results

Blood-brain barrier penetration study

Brief results of this study have been reported previously (10). Concentrations of sarecycline and minocycline in rat blood plasma and brain are included in Table 1 and illustrated in Figure 2. Concentrations of sarecycline and minocycline in rat plasma were similar to each other at each measured time point following IV administration [0.460, 0.217, 0.049 ug/ml (sarecycline) versus 0.333, 0.174 and 0.077 ug/ml (minocycline) at hours 1, 3, and 6, respectively]. However, while detectable concentrations of minocycline in the brain were observed at each measured time point (0.074, 0.139, and 0.068 μg/g at hours 1, 3, and 6, respectively), the level of sarecycline remained below the lower limit of quantitation (0.05 μg/g) in all brain samples at each measured time point.

TABLE 1

Table 1. Concentration of minocycline and sarecycline in plasma (μg/ml) and brain (μg/g) after intravenous administration.

FIGURE 2

Figure 2. (A) Plasma concentrations of sarecycline and minocycline following intravenous administration in rats. (B) Brain concentrations of sarecycline and minocycline following intravenous administration in rats. Dashed line indicates limit of quantitation for plasma (0.025 μg/ml) and brain (0.05 μg/g). *Concentration of sarecycline in the brain was below the limit of quantitation at all time points.

Lipophilicity study

The logD values of sarecycline, minocycline, and doxycycline in octanol/water and chloroform/water solvent systems at 25°C are reported in Table 2. In the octanol/water system, sarecycline was numerically less lipophilic than minocycline at pH 5.5 and 7.4 (−0.16 vs. 0.09 and −0.26 vs. 0.12, respectively) and numerically more lipophilic at pH 3.5 (−0.30 vs. −1.07, respectively). The lipophilicity of doxycycline was between that of sarecycline and minocycline at pH 5.5 and 7.4.

TABLE 2

Table 2. Distribution coefficients (SD) of sarecycline HCl, doxycycline HCl, and minocycline HCl.

In the chloroform/water system, sarecycline was also numerically less lipophilic than minocycline at pH 7.4, was similarly lipophilic at pH 5.5, and was more lipophilic at pH 3.5. Overall, absolute values of logD were higher in the chloroform/water system than in the octanol/water system for sarecycline (pH 3.5, 1.14 vs. −0.30; pH 5.5, 1.48 vs. −0.16; and pH 7.4, 1.46 vs. −0.26, respectively) and minocycline (pH 3.5, 0.07 vs. −1.07; pH 5.5, 1.49 vs. 0.09; and pH 7.4, 1.65 vs. 0.12, respectively), whereas there was little difference in doxycycline logD values between the 2 solvent systems for each pH solution. Differences in logD values observed between the 2 solvent systems may be attributed to the unique hydrogen bonding capabilities of each system (11).

Discussion

To explore potential mechanisms of action associated with the development of vestibular adverse events with certain oral tetracyclines, preclinical in vitro and in vivo analyses were performed to examine the biochemical properties of sarecycline relative to minocycline and doxycycline. In the analysis of in vivo blood-brain barrier penetrance, IV administered minocycline was detectable in the brain in rats, whereas sarecycline was not (10). In the analysis of in vitro lipophilicity, sarecycline had slightly lower logD values compared with doxycycline and minocycline at pH 5.5 and 7.4 in the octanol/water system. Taken together, these results suggest that the lower lipophilicity and reduced brain penetrance of sarecycline relative to minocycline could explain the lower incidence of vestibular adverse events (dizziness, tinnitus, vertigo) seen in sarecycline clinical trials vs. minocycline clinical trials.

In phase 3 clinical trials of sarecycline, overall rates of vestibular adverse events were low (Figure 1) (8, 9). In two identical, randomized, double-blind, placebo-controlled, phase 3 studies of sarecycline (SC1401 and SC1402), rates of the vestibular-related adverse events dizziness and motion sickness were low (≤ 1%) in 994 patients treated with sarecycline (SC1401 = 481; SC1402 = 513) over 12 weeks (8). Additionally, rates of dizziness were lower in patients receiving sarecycline (0.6 and 0.4%) compared with those receiving placebo (1.4 and 0.8%). In both studies, no events of vertigo or tinnitus were reported in either treatment group. Further, in a phase 3 open-label extension study of 483 patients who completed one of the two phase 3 placebo-controlled 12-week trials, dizziness occurred in 0.4% of patients during up to 40 additional weeks of sarecycline treatment (9). Similarly, no events of vertigo or tinnitus were reported in the extension study. Comparatively, in a placebo-controlled, dose-ranging, 12-week trial of extended-release minocycline in 233 patients with moderate to severe facial acne vulgaris, rates of acute vestibular adverse events (dizziness, vertigo, and ringing in the ears) were most commonly reported during the first 5 days of treatment (12, 13). Incidence of acute vestibular adverse events was dose dependent, occurring in 10.2, 23.7, and 28.3% of patients receiving extended-release minocycline 1, 2, or 3 mg/kg, respectively, versus 16.4% in the placebo group during the first 5 days of treatment. Similarly, in a pooled analysis of phase 3 trials of extended-release 1 mg/kg minocycline, rates of acute vestibular adverse events were 9–10.5% during the first 5 days of treatment (13). In a systematic review representing 226,019 pediatric and adult acne patients, Armstrong et al. reported adverse events associated with sarecycline, minocycline, doxycycline and tetracycline, and showed higher rates of acute vestibular events associated with minocycline (∼10%) (14).

In the current analysis, sarecycline was not detected in rat brain samples up to 6 h following IV dosing (10). In contrast, levels of minocycline were detected in rat brain up to 6 h after IV dosing. A limitation of this animal study is the small sample size, which may make it difficult to generalize. However, the trend seen in the results support previous reports that minocycline has high lipid solubility and, thus, may more readily cross the blood-brain barrier compared with other tetracyclines (15). For instance, a previous report in a canine model indicated that the blood-brain penetrance of minocycline was almost threefold higher than that of doxycycline after IV dosing (16). Although no human studies have definitively confirmed this association, the higher brain penetrance of minocycline is suspected to contribute to its higher rates of associated vestibular-related side effects relative to other tetracyclines (10, 16). Minocycline is considered unacceptable for military aviators and is completely restricted for use because of the risk for central nervous system side effects including vestibular side effects such as light-headedness, dizziness and vertigo (17). Conversely, the low rates of vestibular and phototoxic events seen with narrow-spectrum sarecycline make it an acceptable treatment option for the military population and individuals whose lifestyles and careers would suffer because of vestibular side effects.

Previously published logD values of tetracyclines, especially that of minocycline, are variable and inconsistencies permeate in the dermatology literature. For instance, it was previously reported that minocycline was fourfold more lipophilic than doxycycline and 10-fold more lipophilic than tetracycline at a pH of 5.5 (18, 19). Another analysis found that the logD values for minocycline and doxycycline at pH 5.6 were similar (1.11 and 0.95, respectively) (5). The current analysis indicates that in the octanol/water solvent system at pH 5.5 and 7.4, sarecycline (−0.16 and −0.26, respectively) was slightly less lipophilic than both minocycline (0.09 and 0.12, respectively) and doxycycline (0.00 and −0.08, respectively).

A limitation of this analysis is the interpretation of the lipophilicity results. Because octanol/water solvent systems are the most utilized format for lipophilicity analyses (20), this output was determined to provide the more meaningful result in the current analysis rather than the chloroform/water solvent system. However, caution has been advised for basing pharmacological behavior on partition coefficients, limiting the scope of these results (16). Nevertheless, a strength of the current analysis is that the low lipophilicity of sarecycline is supported by data demonstrating a lack of detectable brain penetrance in rats, which further validates the pharmacological profile of sarecycline.

The lower lipophilicity and decreased blood-brain barrier penetration observed for sarecycline ultimately must be explained by chemical structure differences between it and minocycline and doxycycline (21–23). While all three drugs share a common naphthacene four-ring core (21, 22), sarecycline is distinguished by a long C7 extension (7-[[methoxy(methyl)amino]methyl) that provides unique and enhanced ribosomal binding through mRNA contact (Figure 3) (21). The C7 moiety contains an oxygen atom (21), which functions as an acceptor of hydrogen bonds, thereby reducing lipophilicity (24, 25). Additional studies are warranted to investigate the mechanism by which sarecycline is associated with lower rates of vestibular adverse events relative to other tetracyclines, but the chemical structure points toward the C7 moiety oxygen. Thus, the new frontier in this work is specific alterations in the chemical properties of dermatologic drugs have potential to make a major impact on reducing real-world adverse events experienced by patients.

FIGURE 3

Figure 3. Chemical structures of tetracycline-class antibiotics (26).

While high drug lipophilicity in the skin is a desired attribute as it helps in penetrating and accumulating in the lipid-rich pilosebaceous unit—where acne vulgaris therapeutic target, Cutibacterium acnes, resides and proliferates (19)—the increased potential of minocycline to cross the blood-brain barrier compared with other tetracycline-class drugs has served as a purported explanation for the higher rates of vestibular side effects associated with systemic minocycline use in acne treatment, which typically requires a prolonged treatment duration (27–30). Although no confirmatory link has been established, the lack of detectable brain penetrance of sarecycline and its relatively low lipophilicity compared with minocycline as reported in these preclinical studies may correspond with the lower rates of vestibular adverse events observed in clinical trials of sarecycline.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The animal study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC).

Author contributions

AG, CB, and ST: conceptualization. AG and ST: methodology. CB: validation. AG: formal analysis. AG and ST: investigation. AG, RS, and ST: resources. AG and LSG: writing—original draft preparation. AG, AM, LSG, CB, JH, GD, KS, RS, and ST: writing—review and editing. CB, SO, and RS: visualization. AG, RS, and ST: supervision. RS: project administration. All authors have read and agreed to the published version of the manuscript.

Funding

This study received funding from Almirall, LLC. The funder was involved in the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication.

Acknowledgments

Editorial assistance was provided under the direction of the authors by Deirdre Rodeberg, Ph.D., CMPP, and Chris Lawrence, Ph.D., ELS, at MedThink SciCom.

Conflict of interest

AG was a former employee of Almirall, LLC. RS is an employee of Almirall, LLC. ST was an employee of Paratek Pharmaceuticals, Inc. AM has received research funds and honoraria from Almirall, Galderma, Mayne, and Vyne. JH has served as an advisor, investigator, speaker for Almirall, Cutera, EPI, Galderma, Sun, and Vyne. GD has received research funds and honoraria from Almirall, Galderma, Novartis, Amgen, and UCB. LSG has served as an advisor, investigator, and speaker for Almirall, Sun, Galderma, Ortho Derm, Cutera, and EPI Health. CB has served as an investigator for Almirall, a consultant for Abbvie, Almirall, LEO Pharma, Sanofi-Regeneron, UCB, a speaker for and received honoraria from Allergan, Almirall, LEO Pharma, and UCB.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. (2016) 74:945–73.e33. doi: 10.1016/j.jaad.2015.12.037

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Del Rosso JQ. Oral doxycycline in the management of acne vulgaris: current perspectives on clinical use and recent findings with a new double-scored small tablet formulation. J Clin Aesthet Dermatol. (2015) 8:19–26.

PubMed Abstract | Google Scholar

3. Graber EM. Treating acne with the tetracycline class of antibiotics: a review. Dermatol Rev. (2021) 2:321–30. doi: 10.1002/der2.49

CrossRef Full Text | Google Scholar

4. SOLODYN. SOLODYN [package insert]. Scottsdale, AZ: Medicis pharmaceutical corporation (2011).

Google Scholar

5. Colaizzi JL, Klink PR. pH-Partition behavior of tetracyclines. J Pharm Sci. (1969) 58:1184–9. doi: 10.1002/jps.2600581003

PubMed Abstract | CrossRef Full Text | Google Scholar

6. SEYSARA. SEYSARA [package insert]. Exton, PA: Almirall, LLC (2020).

Google Scholar

7. Del Rosso JQ, Stein Gold L, Baldwin H, Harper JC, Zeichner J, Obagi S, et al. Management of truncal acne with oral sarecycline: pooled results from two phase-3 clinical trials. J Drugs Dermatol. (2021) 20:634–40.

PubMed Abstract | Google Scholar

8. Moore A, Green LJ, Bruce S, Sadick N, Tschen E, Werschler P, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris: results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. (2018) 17:987–96.

PubMed Abstract | Google Scholar

9. Pariser DM, Green LJ, Lain EL, Schmitz C, Chinigo AS, McNamee B, et al. Safety and tolerability of sarecycline for the treatment of acne vulgaris: results from a phase III, multicenter, open-label study and a phase I phototoxicity study. J Clin Aesthet Dermatol. (2019) 12:E53–62.

PubMed Abstract | Google Scholar

10. Moore AY, Del Rosso J, Johnson JL, Grada A. Sarecycline: a review of preclinical and clinical evidence. Clin Cosmet Investig Dermatol. (2020) 13:553–60. doi: 10.2147/CCID.S190473

PubMed Abstract | CrossRef Full Text | Google Scholar

11. el Tayar N, Tsai RS, Testa B, Carrupt PA, Leo A. Partitioning of solutes in different solvent systems: the contribution of hydrogen-bonding capacity and polarity. J Pharm Sci. (1991) 80:590–8. doi: 10.1002/jps.2600800619

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Stewart DM, Torok HM, Weiss JS, Plott RT, Solodyn Phase 2 Study Group. Dose-ranging efficacy of new once-daily extended-release minocycline for acne vulgaris. Cutis. (2006) 78(Suppl.):11–20.

PubMed Abstract | Google Scholar

13. Fleischer AB Jr., Dinehart S, Stough D, Plott RT, Solodyn Phase 2 Study Group, Solodyn Phase 3 Study Group. Safety and efficacy of a new extended-release formulation of minocycline. Cutis. (2006) 78(Suppl.):21–31.

Google Scholar

14. Armstrong AW, Hekmatjah J, Kircik LH. Oral tetracyclines and acne: a systematic review for dermatologists. J Drugs Dermatol JDD. (2020) 19:s6–13.

Google Scholar

15. Cunha BA, Baron J, Cunha CB. Similarities and differences between doxycycline and minocycline: clinical and antimicrobial stewardship considerations. Eur J Clin Microbiol Infect Dis. (2018) 37:15–20. doi: 10.1007/s10096-017-3081-x

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Barza M, Brown RB, Shanks C, Gamble C, Weinstein L. Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs. Antimicrob Agents Chemother. (1975) 8:713–20. doi: 10.1128/AAC.8.6.713

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Brahe C, Peters K. Fighting acne for the fighting forces. Cutis. (2020) 106:18–20. doi: 10.12788/cutis.0057

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Cunha BA, Garabedian-Ruffalo SM. Tetracyclines in urology: current concepts. Urology. (1990) 36:548–56. doi: 10.1016/0090-4295(90)80201-W

CrossRef Full Text | Google Scholar

19. Leyden JJ, Del Rosso JQ. Oral antibiotic therapy for acne vulgaris: pharmacokinetic and pharmacodynamic perspectives. J Clin Aesthet Dermatol. (2011) 4:40–7.

Google Scholar

20. Giaginis C, Tsantili-Kakoulidou A. Alternative measures of lipophilicity: from octanol-water partitioning to IAM retention. J Pharm Sci. (2008) 97:2984–3004. doi: 10.1002/jps.21244

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Batool Z, Lomakin IB, Polikanov YS, Bunick CG. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome. Proc Natl Acad Sci U S A. (2020) 117:20530–7. doi: 10.1073/pnas.2008671117

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Nguyen F, Starosta AL, Arenz S, Sohmen D, Donhofer A, Wilson DN. Tetracycline antibiotics and resistance mechanisms. Biol Chem. (2014) 395:559–75. doi: 10.1515/hsz-2013-0292

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Dufès C. Chapter 6: Brain delivery of peptides and proteins. In: CVD Walle editor. Peptide and Protein Delivery. Cambridge, MA: Academic Press (2011). p. 105–22. doi: 10.1016/B978-0-12-384935-9.10006-9

CrossRef Full Text | Google Scholar

24. Chikhale EG, Ng KY, Burton PS, Borchardt RT. Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides. Pharm Res. (1994) 11:412–9. doi: 10.1023/A:1018969222130

CrossRef Full Text | Google Scholar

25. Czyrski A. Determination of the lipophilicity of ibuprofen, naproxen, ketoprofen, and flurbiprofen with thin-layer chromatography. J Chem. (2019) 2019:1–6. doi: 10.1155/2019/3407091

CrossRef Full Text | Google Scholar

26. Bunick CG, Keri J, Tanaka SK, Furey N, Damiani G, Johnson JL, et al. Antibacterial mechanisms and efficacy of sarecycline in animal models of infection and inflammation. Antibiotics (Basel). (2021) 10:439. doi: 10.3390/antibiotics10040439

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Brogden R, Speight T, Avery G. Minocycline: a review of its antibacterial and pharmacokinetic properties and therapeutic use. Drugs. (1975) 9:251–91. doi: 10.2165/00003495-197509040-00005

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Zarzuelo A, Galvez J, Garrido-Mesa N, Garrido-Mesa N. Minocycline: far beyond an antibiotic. Br J Pharmacol. (2013) 169:337–52. doi: 10.1111/bph.12139

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Somech R, Arav-Boger R, Assia A, Spirer Z, Jurgenson U. Complications of minocycline therapy for acne vulgaris: case reports and review of the literature. Pediatric Dermatol. (1999) 16:469–72. doi: 10.1046/j.1525-1470.1999.00106.x

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Ochsendorf F. Minocycline in acne vulgaris. Am J Clin Dermatol. (2010) 11:327–41. doi: 10.2165/11319280-000000000-00000

PubMed Abstract | CrossRef Full Text | Google Scholar