Biochemistry. 1993 Jun 1;32(21):5698-704.
Role of the conserved quartets of residues located in the N- and C-terminal halves of the transposon Tn10-encoded metal-tetracycline/H+ antiporter of Escherichia coli.

Yamaguchi A, Akasaka T, Kimura T, Sakai T, Adachi Y, Sawai T.

Division of Microbial Chemistry, Faculty of Pharmaceutical Sciences, Chiba University, Japan.

In the putative secondary structure of the transposon Tn10-encoded metal-tetracycline/H+ antiporter [Yamaguchi, et al. (1992) J. Biol. Chem. 267, 7490-7498], Tyr50-XXX-Gln54 in transmembrane helix 2 and Gly80-XXX-Asp84 in helix 3 are thought to face each other in the N-terminal region. At the corresponding positions in the C-terminal region, a similar quartet of residues, His257-XXX-Gln261 in helix 8 and Gly281-XXX-Asp285 in helix 9, is also located. The quartets involve the residues Asp84 and Asp285, which have been revealed to be essential for the tetracycline transport function. When Gln54 and Gln261 were replaced with Ala by site-directed mutagenesis, the active tetracycline transport activity decreased to about 10% and 40% of the wild-type level, respectively. The Km values of the Q54A and Q261A mutants for tetracycline were 140 and 160 microM, respectively, which are about 8-fold higher than that of the wild type. Thus, the two Gln residues may contribute to the substrate recognition. On the other hand, the replacement of Gly80 and Gly281 with Leu caused a complete loss of the transport activity, whereas the G80A and G281A mutants retained about 10% and 30% of the activity of the wild-type, respectively, suggesting that a bulky side chain at positions 80 and 281 causes steric hindrance of the transport. The mutation of Tyr50 to Ala or His caused a decrease in activity by a factor of about 3 without a significant change in the Km value, whereas the Y50C mutant showed no transport activity at all.(ABSTRACT TRUNCATED AT 250 WORDS)

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Bangladesh Med Res Counc Bull. 1995 Aug;21(2):77-80.
Triple drug therapy with quinine, cotrimoxazole and tetracycline in the management of cerebral malaria--A review of 254 cases.

Waiz A, Hossain MR, Chakraborty B, Mostafi M.

Bangladesh Armed Forces, Dhaka.

This study reflected that administration of tetracycline along with quinine and cotrimoxazole can reduce mortality from cerebral malaria significantly. In this five year prospective study in an endemic zone, the authors assessed the outcome of treatment with or without tetracycline among 254 cases of cerebral malaria. 100 patients were treated with quinine and cotrimoxazole and 154 patients were given triple therapy-quinine, cotrimoxazole and tetracycline. Fatality in group without tetracycline was 18%, whereas in the tetracycline group it was 12.33%. One interesting observation was that the parasite count was not proportional to the severity of disease. Out of 254 patients of this series, 136 patients (53.54%) had low parasite count (less than 1,000/cumm) and only 26 patients (10.23%) had infinity count. Quinine induced cardiac arrhythmia or hypoglycaemia was not seen in any patient.

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Int J Rad Appl Instrum B. 1986;13(6):611-5.
99mTc-tetracycline radiopharmaceutical: physical chemistry study related to the preparation and reaction products and thermodynamic stability.

Ibanez Zurriaga A, Garcia Domenech R, Farga Marti A, Galvez Alvarez J.

The labelling of tetracycline hydrochloride with 99mTc at neutral pH, using Sn2+ as reducing agent, has been investigated by chromatography, using a 4:1:5 n-butanol:acetic acid:H2O mixture as developing agent, with Whatman paper No 3. In such conditions, reduced 99mTc remained at the origin, while labelled 99mTc migrates at Rf approximately equal to 0.6. Radiochromatographic and u.v.-visible spectrophotometric results, demonstrated that the higher the tetracycline concentration the higher was the labelling of 99mTc to that ligand, obtaining a 50% labelling when the molar ratio of tetracycline:Sn2+ was approximately 20:1, independent of the Tc concentration level. The Tc oxidation state in the radiopharmaceutical is +4, deduced from iodimetric and radiometric techniques. Furthermore, it seems that time does not influence labelling, while pH does. The maximum labelling level occurs at physiological pH. The thermodynamic study performed with the radiopharmaceutical formation shows that the Tc-tetracycline complex has a 1:1 stoichiometry, thus a low stability constant (about 2 X 10(2)).

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J Pharm Biomed Anal. 1994 Dec;12(12):1483-8.
Evaluation of tetracycline raw materials and finished products found on the Kenyan market.

Muritu JW, Kibwage IO, Maitai CK, Hoogmartens J.

Department of Pharmacy, College of Health Sciences, University of Nairobi, Kenya.

Contents of tetracycline, its degradation products (epitetracycline, epianhydrotetracycline, anhydrotetracycline) and a fermentation impurity (2-acetyl-2-decarboxamidotetracycline) were determined in four raw materials, 12 batches of six ointment products, four eye ointment products and nine batches of five capsule products, all sampled from the Kenyan market. The analytical method was liquid chromatography on a column packed with a poly(styrenedivinyl-benzene) material (8-microns PLRP-S 100 A). All raw materials and finished products had tetracycline contents and impurity levels within the prescribed compendial limits.

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J Oral Maxillofac Surg. 1990 Aug;48(8):808-12.
Foreign body giant cell reaction related to placement of tetracycline-treated polylactic acid: report of 18 cases.

Moore JW, Brekke JH.

Presented are 18 cases of foreign body giant cell reaction in mandibular third molar extraction wounds previously treated with 40 mg of dry tetracycline powder carried into the wound with a biodegradable polymer dressing. The lesions vary in intensity from local, soft tissue granulomas to osteolytic, central bone pathologies. Several reports of foreign body giant cell reaction to insoluble tetracycline preparations are cited, along with a brief review of the relationship between myospherulosis and various formulations of tetracycline powder in petroleum-based carrier vehicles. The authors suggest that the foreign body giant cell lesions reported here were initiated by micron-sized particles of insoluble tetracycline powder and were further aggravated by certain hydrophobic characteristics of the associated biodegradeable polymer. The authors caution against use of dry, powdered forms of topical antibiotics in fresh dental extraction wounds.

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J Biomed Mater Res. 2000 Sep 5;51(3):391-7.
Enhanced guided bone regeneration by controlled tetracycline release from poly(L-lactide) barrier membranes.

Park YJ, Lee YM, Park SN, Lee JY, Ku Y, Chung CP, Lee SJ.

Department of Industrial Pharmacy, College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-Ku, 120-750 Seoul, South Korea.

With the aim of providing effective periodontal therapeutic modality, drug-releasing membranes for guided tissue regeneration (GTR) were developed. As GTR membranes, biodegradable barrier membranes composed of porous poly(L-lactide) (PLLA) films cast on poly(glycolide) (PGA) meshes were fabricated using an in-air drying phase inversion technique. PLLA was dissolved in methylene chloride-ethylacetate mixtures, cast on knitted PGA mesh, and then air-dried. Tetracycline, which is used in periodontal therapy because of its antibacterial activity and tissue regenerating effects, including osteoblast chemotactic effect and anti-collagenolytic activity, was incorporated into the membranes by adding it to PLLA solutions. The guided bone regenerating potential of tetracycline-loaded membranes was evaluated using release kinetics both in vitro and in vivo, biodegradation tests, and cell attachment tests. Homogeneous pores were generated both at the surface and in a sublayer of the membranes. The release kinetics of tetracycline depended mainly upon the hydrophilicity of tetracycline and the porosity of the membrane. The release rate further could be controlled by loaded drug contents. The release of tetracycline was appropriate for maintaining anti-microbial activity and for its tissue-regenerating potential. The membranes retained a proper degradation property, maintaining their mechanical integrity for the barrier function for 4 weeks. Tetracycline-loaded membranes induced increased cell attachment levels compared with those of unloaded membranes. Tetracycline-loaded membranes markedly increased new bone formation in rat calvarial defects and induced bony reunion after 2 weeks of implantation. These results suggest that tetracycline-loaded PLLA membranes potentially enhance guided tissue regenerative efficacy. Copyright 2000 John Wiley & Sons, Inc.

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FEBS Lett. 1997 Jun 30;410(2-3):259-64.
Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines.

Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG, Abramson SB.

Department of Rheumatology and Medicine, Hospital for Joint Diseases, New York, NY 10003, USA.

Chemically modified tetracyclines [CMT-3 (IC50 approximately 6-13 microM = approximately 2.5-5 microg/ml) and CMT-8 (IC50 approximately 26 microM = 10 microg/ml), but not CMT-1, -2 or -5], which lack anti-microbial activity, inhibited nitrite production in LPS-stimulated macrophages. Unlike competitive inhibitors of L-arginine which inhibited the specific activity of inducible nitric oxide synthase (iNOS) in cell-free extracts, CMTs exerted no such direct effect on the enzyme. CMTs could, however, be shown to inhibit both iNOS mRNA accumulation and protein expression in LPS-stimulated cells. Tetracyclines (doxycycline and CMT-3) unlike hydrocortisone had no significant effect on murine macrophages transfected with iNOS promoter (tagged to a luciferase reporter gene) in the presence of LPS. However, doxycycline and CMT-3 augmented iNOS mRNA degradation, in LPS-stimulated murine macrophages. These studies show a novel mechanism of action of tetracyclines which harbours properties to increase iNOS mRNA degradation and decrease iNOS protein expression and nitric oxide production in macrophages. This property of tetracyclines may have beneficial effects in the treatment of various diseases where excess nitric oxide has been implicated in the pathophysiology of these diseases.

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hsc.vcu.edu

To evaluate the utility of tetracycline gene regulation in the study of human cytomegalovirus gene functions, expression of luciferase under the control of tetracycline-regulatable promoters was studied following transient plasmid transfections and from within recombinant human cytomegalovirus genomes. The tetracycline-regulatable promoter PhCMV*-1 contains sequences from the human cytomegalovirus ie1/ie2 promoter and seven upstream tet operator sites which bind the activator protein tTA only in the absence of tetracycline (Gossen and Bujard (1992). Proc. Natl. Acad. Sci. USA 89, 5547-5551). Two modifications of PhCMV*-1 were also studied: P1129, in which the tet operator sites were reduced from seven to one; and P1125, in which human cytomegalovirus sequences were replaced by adenovirus major late promoter and terminal deoxynucleotidyltransferase initiator sequences. In transient assays, PhCMV*-1 and P1125 exhibited modest differential regulation but were strongly activated by viral infection. P1129 exhibited less viral activation and narrower regulation. In the viral genome, PhCMV*-1 exhibited regulation up to 7-fold during late times of infection, whereas P1125 displayed nearly 100-fold regulation. Regulation of P1125 was fully reversed within 12 to 24 h of adding or removing tetracycline. These results suggest that P1125 may provide sufficient conditional expression to effectively regulate human cytomegalovirus late genes. Copyright 1999 Academic Press.

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