Home
Up

Rolitetracycline

A pyrrolidinylmethyl tetracycline. It is a prodrug of tetracycline obtained by reaction of amide group with pyrrolidine and formaldehyde to provide the corresponding mannich base. Rolitetracycline is more hydrophilic than tetracycline and has sufficient water solubility to allow intravenous administration.

The spectrum of activity, the resistance pattern and therapeutic use resemble those of tetracycline. It is therefore used to treat infections sustained by Gram positive and gram negative bacteria, aerobes and anaerobes including Brucella and E.coli [1]. The drug is used preferentially when it is necessary to reach an high plasma concentration or when the oral therapy is not advisable.

Therapeutic use

Rolitetracycline is a broad-spectrum antibiotic used in cases needing high concentrations or when oral administration is impractical. Rolitetracycline is used for the treatment of brucellosis [2], upper respiratory tract infections and sinusitis [3], pulmonary infections [4-6]. In the literature is also reported the use in the treatment of sexually transmitted disease, including gonorrhoea [7,8], intestinal infections [9,10], bone [11] and biliary infections [4].

Dosage and Administration

Adult: 350mg intramuscular injection; 275mg i.v. (2-3minutes infusion) once a day. For severe infections the dose can be administered up to three times a day.

Toxicology

After parenteral injections with rolitetracycline, in the treatment of infections sustained by highly sensitive bacteria, tremors and rigor have been observed as a manifestation of Herxheimer-like reaction. After the injection of rolitetracycline an unpleasant taste similar to ether has been reported.

Experimental studies on piglets have shown that high doses of rolitetracycline (10-20 times above therapeutic doses) can have vascular effect with a transient increase of arterial blood pressure and ECG alterations, in particular the PQ interval [12]. These effects are not observed at normal therapeutic doses [13]. Rapid endovenous injection can cause transient vertigo, heat flushes, facial redness and occasionally perifal circulatory insufficiency.
Studies in mice have demonstrated that rolitetracycline can increase ematic concentration of AST, ALT and bilirubine [14]. Endoveous administration of rolitetracycline can exacerbate myasthenia gravis symptoms [15,16] possibly due to the presence of magnesium ions in the formulation [17,18].


LD50=262 mg/kg (I.P. in rat), LD50=91 mg/kg (i.v. in rat) [19].

Pharmacokinetic

Bioavailability (iv) 100
Metabolism  
Cmax (mg/ml) 2-6 (IM) 20 (iv) (350mg/dose)
tmax (hrs) -
Half-life 5-8
Eliminiation rate Constant  
Excretion urinary (>50%) biliary [20-22]
Protein binding 50%

Absorption

 

Distribution

 

Elimination

 

Metabolism

 

Mechanism of action

Rolitetracycline passively diffuses through porin channels in the bacterial membrane and reversibly binds to the 30S ribosomal subunit, preventing binding of tRNA to the mRNA-ribosome complex, and thus interfering with protein synthesis.


Medicinal Chemistry

CAS number: 751-97-3 EINECS:

Molecular Formula:  C27H33N3O8

Average mass: 527.566223 Da

Monoisotopic mass: 527.226746 Da

Systematic name: (4S,4aS,5aS,6S,12aS)-4-(Dimethylamino)-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-N-(1-pyrrolidinylmethyl)-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide

SMILES: O=C(NCN1CCCC1)\C5=C(/O)[C@@H](N(C)C)[C@@H]4C[C@H]3C(\C(=O)c2c(O)cccc2[C@@]3(C)O)=C(\O)[C@]4(O)C5=O

Std. InChI: 1S/C27H33N3O8/c1-26(37)13-7-6-8-16(31)17(13)21(32)18-14(26)11-15-20(29(2)3)22(33)19(24(35)27(15,38)23(18)34)25(36)28-12-30-9-4-5-10-30/h6-8,14-15,20,31,33-34,37-38H,4-5,9-12H2,1-3H3,(H,28,36)/t14-,15-,20-,26+,27-/m0/s1

ACD/LogP: -0.133 # of Rule of 5 Violations: 3
ACD/LogD (pH 5.5): -3.60 ACD/LogD (pH 7.4): -2.95
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 11 #H bond donors: 6
#Freely Rotating Bonds: 9 Polar Surface Area: 170.87 Å2
Index of Refraction: 1.712 Molar Refractivity: 134.111 cm3
Molar Volume: 342.18 cm3 Polarizability: 53.166 10-24cm3
Surface Tension: 89.2730026245117 dyne/cm Density: 1.542 g/cm3
Flash Point: 452.363 °C Enthalpy of Vaporization: 125.598 kJ/mol
Boiling Point: 824.37 °C at 760 mmHg Vapour Pressure: 0 mmHg at 25°C

Aspect: Fine, pale yellow needles,

Melting point: dec 162-165°.

Water solubility: 1.25 g/ml at 25°C.

Rolitetracycline is unstable in aqueous solutions [23]. At room temperature >50% of the dose is hidrolyzed in 3 hrs, and at 5°C there is a 15% hydrosysis in 21-25 hrs.

Rolitetracycline must be stored in tightly closed containers, protected from light.


1. ZAKI, S., AS. ELYAN; A. EL-ANWAR. The effect of I. V. Reverin on aerobic intestinal flora.. J Egypt Med Assoc 1962, 45, 976-81.

2. Korbelár J. Rolitetracycline (reverin) in the treatment of brucellosis. Cas. Lek. Cesk. 1969, 108, (16), 474–6.

3. Graeber F, Zaloudek D. Ambulatory therapy of sinusitis with Reverin in otorhinolaryngologic practice. MMW Munch Med Wochenschr 1981, 123, (2), 59–60.

4. von Stransky B, Bottermann P. Rolitetracycline in lung and biliary tract infections. MMW Munch Med Wochenschr 1979, 121, (11), 397–8.

5. FROSIO, G. Indications for the use of intravenous pyrrolidinomethyltetracycline in the therapy of acute bronchopleuro-pulmonary disease. Osp Maggiore 1963, 51, 126-47.

6. BONERA, E., M. BRUNELLI. Note on the clinical use of pyrrolidinomethyltetracycline by venous route in chronic bronchopulmonary inflammation. Clin Ter 1962, 23, 539-44.

7. Wilcox RR. Rolitetracycline by injection and tetracycline phosphate complex by mouth given in a single session in the treatment of gonorrhoea in males. Acta Derm. Venereol. 1970, 50, (2), 154–6.

8. Danda J, Dbalý V, Hamáková K, Hejzlar M, Klíma J, Novotný F. One-day treatment of gonorrhoea by rolitetracycline (RTTC). Cesk Dermatol 1979, 54, (2), 98–100.

9. Lindahl F. [Acute perforative appendicitis and periappendicular abscess. Treatment with colistin and rolitetracycline]. Ugeskr. Laeg. 1969, 131, (39), 1637–40.

10. PARENTI, C. PYRROLIDINOMETHYLTETRACYCLINE IN SEPTIC SURGERY. Gazz Int Med Chir 1964, 69, 1066-82.

11. Leblanc JP, Rousseau B, Segal P, Gerard Y, Choisy H, Enger A. Treatment of bone infections using intra-arterial injections of rolitetracycline. Therapie 1975, 30, (5), 685–94.

12. Tauberger G, Schoog M, Mehren W, Mergler G, Moussawi M. [On the circulation compatibility of doxycycline and rolitetracycline in conscious minipigs (author's transl)]. Arzneimittelforschung 1978, 28, (12), 2235–7.

13. Schölkens B, Gerhards H, Lindner E. Circulatory effects of intravenously administered rolitetracycline and other tetracyclines in animal experiments. Arzneimittelforschung 1974, 24, (3), 312–7.

14. Böcker R, Estler CJ, Müller S, Pfandzelter C, Spachmüller B. Comparative evaluation of the effects of tetracycline, rolitetracycline and doxycycline on some blood parameters related to liver function. Arzneimittelforschung 1982, 32, (3), 237–41.

15. Wullen F, Kast G, Bruck A. [On side-effects of tetracycline administration in myasthenic patients]. Dtsch. Med. Wochenschr. 1967, 92. (14), 667–9.

16. Igata A. Antibiotics and myasthenia gravis. Shinkei Kenkyu No Shimpo 1971, 15, (4), 910–3

17. Hashimoto Y, Sasaki H, Yoshinari M, Iwatsuki K. Myasthenia gravis and antibiotics. Masui 1977, 26, (2), 143–8.

18. Gibbels E. Further observations on side effects of intravenous administration of reverin in myasthenia gravis pseudoparalytica. Dtsch. Med. Wochenschr. 1967, 92, (25), 1153–4.

19. Goldenthal EI. A compilation of LD50 values in newborn and adult animals. Toxicol. Appl. Pharmacol. 1971, 18, (1), 185–207.

20. Dimmling, T., O. Vanderbeke. Pharmacokinetics after oral and intravenous administration of tetracycline compounds. Med Klin 1975, 70, (7), 279-85.

21. Böcker, R., CJ. Estler. Distribution of pyrrolidinomethyl-tetracycline (rolitetracycline) and tetracycline in blood and various organs of mice measured by high pressure liquid chromatography. Arzneimittelforschung 1979, 29, (11), 1693-5.

22. Butterfield, AG., DW. Hughes; WL. Wilson; NJ. Pound. Simultaneous high-speed liquid chromatographic determination of tetracycline and rolitetracycline in rolitetracycline formulations. J Pharm Sci 1975, 64, (2), 316-20.

23. Hughes DW, Wilson WL, Butterfield AG, Pound NJ. Stability of rolitetracycline in aqueous solution. J. Pharm. Pharmacol. 1974, 26, (1), 79–80

 

     Hit Counter

 

Send mail to stefano.biondi@innovativesolution.it with questions or comments about this web site.
Copyright © 2010 Innovative Solution di Biondi Stefano