Details of the Drug Combination

General Information of Drug Combination (ID: DCA3SJX)

• Drug Combination Name: Ciprofloxacin XR + Doxycycline
• Indication: Diabetic Foot Ulcers; Status: Phase 1 [1]
• Component Drugs:
  Ciprofloxacin XR (DM2NLS9): Small molecular drug
  Doxycycline (DM7ICNU): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ciprofloxacin XR

Disease Entry	ICD 11	Status	REF
Acute gonococcal cervicitis	N.A.	Approved	[2]
Acute maxillary sinusitis	N.A.	Approved	[2]
Anthrax	1B97	Approved	[2]
Bacillary dysentery	1A02	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Chancroid	N.A.	Approved	[2]
Crohn disease	DD70	Approved	[2]
Cystitis	GC00	Approved	[2]
Fever	MG26	Approved	[2]
Gram-positive bacterial infection	1B74-1G40	Approved	[4]
Inflammation	1A00-CA43.1	Approved	[2]
Malignant otitis externa caused by Pseudomonas aeruginosa	N.A.	Approved	[2]
Prostatitis	N.A.	Approved	[5]
Staphylococcus aureus infection	N.A.	Approved	[2]
Traveler's diarrhea	ME05.1	Approved	[2]
Cystic fibrosis	CA25	Phase 2	[6]
Biliary cancer	2E92.7	Phase 1	[7]

Ciprofloxacin XR Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial DNA gyrase (Bact gyrase)	TTN6J5F	GYRA_STAAU; GYRB_STAAU	Modulator	[11]
Bacterial Penicillin binding protein (Bact PBP)	TTJP4SM	NOUNIPROTAC	Inhibitor	[4]
Staphylococcus Topoisomerase IV (Stap-coc parC)	TTIXTO3	PARC_STAAS	Modulator	[11]
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[12]

Ciprofloxacin XR Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[13]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[14]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[16]

Ciprofloxacin XR Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[17]
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Decreases Expression	[17]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Decreases Expression	[17]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Increases Expression	[17]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[17]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Increases Expression	[17]
Homeobox protein NANOG (NANOG)	OTUEY1FM	NANOG_HUMAN	Increases Expression	[17]
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Decreases Expression	[18]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[19]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[20]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Increases Expression	[20]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Secretion	[22]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[23]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[24]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[24]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[21]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Decreases Expression	[25]
Aspartate aminotransferase, mitochondrial (GOT2)	OT6XBWN0	AATM_HUMAN	Increases ADR	[26]
DNA gyrase subunit A (gyrA)	OTFI7I9Z	GYRA_AERSA	Increases ADR	[26]
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2)	OTPGYWKC	NOD2_HUMAN	Decreases Response To Substance	[27]

Indication(s) of Doxycycline

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[8]
Actinomycosis	N.A.	Approved	[8]
Acute gonococcal cervicitis	N.A.	Approved	[8]
Acute gonococcal epididymo-orchitis	N.A.	Approved	[8]
Advanced gum disease	DA0D	Approved	[9]
Anthrax	1B97	Approved	[8]
Bartonellosis	N.A.	Approved	[8]
Boutonneuse fever	N.A.	Approved	[8]
Brill-Zinsser disease	N.A.	Approved	[8]
Bronchitis	CA20	Approved	[8]
Brucellosis	N.A.	Approved	[8]
Chancroid	N.A.	Approved	[8]
Chlamydiaceae infections	N.A.	Approved	[8]
Chronic periodontitis	DA0C.Y	Approved	[9]
Colorectal carcinoma	N.A.	Approved	[8]
Cutaneous anthrax	N.A.	Approved	[8]
Endemic typhus	N.A.	Approved	[8]
Epidemic louse-borne typhus	N.A.	Approved	[8]
Gastrointestinal anthrax	N.A.	Approved	[8]
Inhalational anthrax	N.A.	Approved	[8]
Listeriosis	N.A.	Approved	[8]
Lymphogranuloma venereum	N.A.	Approved	[8]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[8]
Ornithosis	N.A.	Approved	[8]
Q fever	N.A.	Approved	[8]
Relapsing fever	N.A.	Approved	[8]
Rickettsialpox	N.A.	Approved	[8]
Rickettsiosis	N.A.	Approved	[8]
Rocky mountain spotted fever	N.A.	Approved	[8]
Syphilis	N.A.	Approved	[8]
Trachoma	N.A.	Approved	[8]
Tularemia	1B94	Approved	[8]
Typhus	N.A.	Approved	[8]
Yaws	N.A.	Approved	[8]
Diabetic foot ulcer	BD54	Phase 2	[10]
Sinusitis	CA0A.Z	Investigative	[8]
Vibrio cholerae infection	1A00	Investigative	[8]

Doxycycline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 30S ribosomal RNA (Bact 30S rRNA)	TTOVFH2	NOUNIPROTAC	Modulator	[11]

Doxycycline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[29]

Doxycycline Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[30]

Doxycycline Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[31]
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Decreases Activity	[32]
Neutrophil collagenase (MMP8)	OTZXH19L	MMP8_HUMAN	Decreases Activity	[32]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[33]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Crohn's Disease	DCTTCKY	N. A.	Phase 2	[34]
Rhinoscleroma	DCKLMVK	N. A.	Phase 1	[35]

References

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• [2] A standard database for drug repositioning. Sci Data. 2017 Mar 14;4:170029.
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Emerging drugs for bacterial urinary tract infections. Expert Opin Emerg Drugs. 2005 May;10(2):275-98.
• [5] Comparison of a 3-day with a 1-day regimen of an extended-release formulation of ciprofloxacin as antimicrobial prophylaxis for patients undergoing transrectal needle biopsy of the prostate. BJU Int. 2007 Jul;100(1):51-7.
• [6] Inhaled Ciprofloxacin for the Management of Infections in Non-Cystic Fibrosis Bronchiectasis (BE) Patients
• [7] Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Cancer Chemother Pharmacol. 2006 Jan;57(2):171-9.
• [8] Doxycycline FDA Label
• [9] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6464).
• [10] ClinicalTrials.gov (NCT00764361) Safety Study of Topical Doxycycline Gel for Adult Diabetic Lower Extremity Ulcers. U.S. National Institutes of Health.
• [11] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [12] Loss of folylpoly-gamma-glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation-dependent novel antifolates in multiple human leukemia sublines. Int J Cancer. 2003 Feb 20;103(5):587-99.
• [13] Fluoroquinolone efflux mediated by ABC transporters. J Pharm Sci. 2008 Sep;97(9):3483-93.
• [14] Identification of the efflux transporter of the fluoroquinolone antibiotic ciprofloxacin in murine macrophages: studies with ciprofloxacin-resistant cells. Antimicrob Agents Chemother. 2009 Jun;53(6):2410-6.
• [15] Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol Pharmacol. 2008 Jul;74(1):122-31.
• [16] Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol. 2010 Nov;70(5):645-55.
• [17] Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism. Chem Biol Interact. 2016 Apr 25;250:1-11.
• [18] The role of MITF and Mcl-1 proteins in the antiproliferative and proapoptotic effect of ciprofloxacin in amelanotic melanoma cells: In silico and in vitro study. Toxicol In Vitro. 2020 Aug;66:104884. doi: 10.1016/j.tiv.2020.104884. Epub 2020 May 8.
• [19] Ciprofloxacin decreases survival in HT-29 cells via the induction of TGF-beta1 secretion and enhances the anti-proliferative effect of 5-fluorouracil. Br J Pharmacol. 2009 Jun;157(3):362-70. doi: 10.1111/j.1476-5381.2009.00161.x. Epub 2009 Apr 9.
• [20] Ciprofloxacin enhances the stimulation of matrix metalloproteinase 3 expression by interleukin-1beta in human tendon-derived cells. A potential mechanism of fluoroquinolone-induced tendinopathy. Arthritis Rheum. 2002 Nov;46(11):3034-40. doi: 10.1002/art.10617.
• [21] Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clin Cancer Res. 2000 Mar;6(3):891-900.
• [22] Quinolones as enhancers of camptothecin-induced cytotoxic and anti-topoisomerase I effects. Biochem Pharmacol. 2008 Mar 15;75(6):1272-81. doi: 10.1016/j.bcp.2007.11.014. Epub 2007 Dec 3.
• [23] Disturbance of cellular glucose transport by two prevalently used fluoroquinolone antibiotics ciprofloxacin and levofloxacin involves glucose transporter type 1. Toxicol Lett. 2009 Jan 30;184(2):81-4. doi: 10.1016/j.toxlet.2008.10.017. Epub 2008 Oct 28.
• [24] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [25] Contrasting effects of fluoroquinolone antibiotics on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, in human tendon-derived cells. Rheumatology (Oxford). 2005 Dec;44(12):1514-7. doi: 10.1093/rheumatology/kei087. Epub 2005 Sep 7.
• [26] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [27] NOD2/CARD15 gene variants are linked to failure of antibiotic treatment in perianal fistulating Crohn's disease. Am J Gastroenterol. 2008 May;103(5):1197-202. doi: 10.1111/j.1572-0241.2007.01741.x. Epub 2008 Mar 26.
• [28] Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):293-301.
• [29] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [30] A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):272-8.
• [31] Functional and histochemical analysis of MDR3 P-glycoprotein in a tetracycline-controlled gene expression system. Eur J Med Res. 2000 Dec 29;5(12):517-22.
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• [33] Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion. Toxicol Sci. 2010 Jul;116(1):140-50. doi: 10.1093/toxsci/kfq085. Epub 2010 Mar 25.
• [34] ClinicalTrials.gov (NCT01783106) Antibiotics and Hydroxychloroquine in Crohn's
• [35] ClinicalTrials.gov (NCT05431673) Efficacy Of Doxycycline & Versus Rifampin In Treatment Of Rhinoscleroma