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BATINA R

TINIDAZOLE TABLET 500mg TINIDAZOLE SUSPENSION 500mg / 5ml TINIDAZOLE Injection 400mg / 100ml, 800mg / 200ml

The Platinum Standard for Treatment of

Anaerobic

Bacterial

BAKAN GIZO UK LTD. ...Innovative Healthcare Solutions.

Infections

...think convenience, think Batina

BATINA R

THE PLATINUM STANDARD FOR TREATMENT OF

ANAEROBIC BACTERIAL INFECTIONS

HISTORY HISTORY: Batina contains Tinidazole (2nd Generation 5-nitroimidazole) as the active ingredient.

Below is a representative of its discovery and that of the other members of the class of 5-nitroimidazole showing alongside their side chain / chemical name.

AZOMYCIN (Isolated from streptomyces bacteria, effective on Trichomonas but too Toxic).

Mechanism of action: Tinidazole is taken up by diffusion and selectively absorbed by anaerobic bacteria and some selective protozoa. The nitro group is emzymatically reduced by ferrodoxin to release nitro radical anion which removes electron from the DNA of the selective bacteria and protozoa. This reduction causes the production of a cytotoxic intermediate product, which binds to anaerobic cells, and allows for selective accumulation in anaerobes DNA

METRONIDAZOLE (1st Generation) ETHANOL/2-(2-Methyl-5-nitroimidazol-I-yl) ethanol

Removes an electron from DNA

TINIDAZOLE (2nd Generation) ETHYLSULPHONYLETHYL/I -(2-(2-Ethylsulphonylethy (ethyl)-2-Methyl-5nitroimidazole SECNIDAZOLE (3rd Generation) 1-(2-Methyl-5-itroimidazol-l-yl) propan-2-ol

-

CH2 CH -SO2 CH -CH3 2

TINIDAZOLE

C N O2N-C C CH3 N

C N O2N-C C CH3 N

CH2 CH -CH3 OH

CH2 CH-CH2CI OH

ORNIDAZOLE

STRUCTURE ACTIVITY RELATIONSHIP In vitro studies on drug-sensitive and drug-resistant protozoan parasites indicate that the nitro group at the position 5 of metronidazole is essential for activity and that substitution at position 2 of the imidazole ring enhances the resonance conjugation of the chemical structure thereby increases antiprotozoal activity (Upcroft et al., 1999).

40µg/ml plasma concentration is achieved in 2hrs after a single 2g Oral dose or 1.6g I.V, falling to about 10µg/ml at 24hrs, and 2.5µg/ml at 48hrs; conc. above 8µg/ml (>MIC) are maintained by a daily dose of 1g oral or 800mg I.V dose.

Widely distributed and similar plasma concentrations have been achieved in bile, breastmilk, CSF, saliva, vaginal secretions and a variety of body tissues; it crosses the placenta readily.

Only 12% is reported to be bound to plasma proteins. An active hydroxyl metabolite has been identified.

BATINA DISTRIBUTION - SALIVARY GLANDS

Methyl Group

o N

o

s

N N+

N

o o

oH

N

Parotid gland Tongue

Imidazole Ring

o

N+

o

Sublingual gland Submandibular gland

Nitro Group

Tinidazole

R-NHOH

Batina is administered as in 1 and 2 above.

Tinidazole in daily doses of up to 2g is free of toxicity, exhibiting a half - life of 12-14 hours (doubling that of Metronidazole).

CH3

N

O2N

METRONIDAZOLE

SECDNIDAZOLE

R-NO

Nitroradical anion DNA damage produced by reduced nitro products of batina

N

2

CH2CH2-OH

R-NO2 H

R-NO2

PHARMACOKINETICS Administration 1. Oral: Almost complete Absorption 2. Intravenous: Complete Absorption 3. Vaginal: BA 20-25%

ORNIDAZOLE (4th Generation) 1-Chloro-3-(2-Methyl-5-nitoimidazole-l-yl)propan-2-ol

H-C -N C-CH3 O2N C N -

+ DNA

Metronidazole

Concentration are detectable in saliva up to 7days after 1g single dose administration when serum concentrations are not identified.

After 1g single dose administration, concentrations in mixed, parotid and submandibular saliva were approximately 10µg/ml at 1hr, 20µg/ml from 3 to 6hrs and 10µg/ml at 24hrs respectively.

SPECTRUM OF ACTIVITY OF BATINA 1. Bactericidal on anaerobic bacteria Active on sporulated Gram (+) bacteria Active on non sporulated Gram (-) anaerobic bacteria (clostridium and bacteroides) Inactive on aerobic bacteria except in H. Pylori.

Bacteroides fragilis, Prevotella Porphyromonas spp, Fusobacterium spp, Bilophila spp Sutterella spp Peptostreptococcus spp Clostridium spp.

DRUG INTERACTIONS With Disulfiram; risk of delirious episodes, with alcohol; Disulfiram like effects; precautions with oral anticoagulants increase anti-vitamin K effects.

CURE RATE OF 5-NITROMIDAZOLES IN BACTERIA VAGINOSIS AT FOUR WEEKS.

Name of medicine

Cure rate by Amsel’s criteria (%)

Metronidazole Tinidazole Secnidazole Ornidazole

Actinomyces spp, Propionibacterium spp, Eubacterium spp Lactobacillus spp, Bifidobacterium spp, Veillonella spp Staphylococcus aureus Helicobacter pylori

2. Active on selective protozoas; namely Entamoeba Histolytica Lambia, Trihomonas Vaginalis.

2. Robson RA, et al. Tinidazole Pharmacokinetics in severe renal failure Clinical Pharmacology 1984:9:88-94. PubMed..

Giardia

METABOLISM AND ELIMINATION Hepatic metabolism, an Active Hydoxyl metabolite has been identified.

Unchanged drugs and metabolite are excreted in the urine and to a lesser extent, in feaces ADVERSE EFFECTS Frequently: GIT disturbance, nausea, gastralgia, metallic taste, glossitis, stomatitis. Urticaria Moderately: Leucopenia, reversible on stoppage of Tinidazole rarely: Vertigo, ataxia, Paraesthesia

67/86 (77.9) 84/86 (97.7) 69/86 (80.2) 84/86 (97.7)

P value P<0.001 P<0.001

ABSTRACT TREATMENT OF AMOEBIC LIVER ABSCESS WITH TINIDAZOLE AND METRONIDAZOLE. 20 patients with amoebic liver abscess, confirmed by aspiration of typical amoebic 'pus', were treated in random order with either tinidazole or metronidazole in a dose of 2g once daily for 2 days. Clinical, radiological, and biochemical follow-up was done for 1 month. One patient given metronidazole absconded and 19 completed the trial. Complete recovery occured in all 10 patients given tinidazole but in only 5 of the 9 given metronidazole (p=0.05). Patients on tinidazole required repeated aspiration less frequently than those on metronidazole. Mild gastrointestinal side effects occurred in 1 patient on metronidazole but none on tinidazole. From the present study, tinidazole appears to be a more effective, better tolerated drug with a more rapid therapeutic effect than metronidazole..

Khakhani RC,Garud AD, Deadhar KP, Sureka SB, Kulkami M, Damle VB. Drugs 1987;15 Suppl 1:23-5 ADVANTAGES OF BATINA OVER METRONIDAZOLE

Better pharmacokinetic and pharmacodynamic profile Better safety and tolerability profile

(%) of Patients

CAUTIONS/CONTRA-INDICATIONS Disulfiram-like reaction with alcohol. Hepatic impairment and hepatic encephalopathy; pregnancy and breast feeding (as with all other 5nitroimidazoles). In patients with previous history of hypersensitivity to Tinidazole or other 5-nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to steven-johnson syndrome. The American Academy of Pediatrics considers that the use of 5-nitroimidazoles by mothers during breast feeding of neonates may be of concern, since they are mutagenic in vitro. Following single-does therapy, breast feeding may be discontinued for 24 hours or more to allow excretion of the dose. i. American Academy of Pediatrics, the transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108:776-89. PubMed Correction; 1029

80

2g tinidazole (n=122) 62.4%

2g metronidazole (n=101)

60 40 20

21.8%

21.3% 6.6%

0 Nausea

1.6%

Vomitting

6.9%

Diarrhea

Manaorama HT, Shenoy DR. Single-dose oral treatment of vaginal trichomoniasis With tinidazole and metronidazole. J Int Med 1978;6(1):46-9

RENAL IMPAIRMENT Single-dose studies indicate that the pharmacokinetics of tinidazole in patients with chronic renal failure are not significantly different from those in healthy subjects and that no modification of tinidazole dosage is necessary.

However, tinidazole is rapidly removed by haemodialysis. (1,2) so need to readminister after dialysis.

1. Flouvat BL, et al, Pharmacokinetics of tinidazole in chronic renal failure and in patients an haemodialysis. Br J Clin Pharmacol 1983; 15:735-41.

PubMed.

Preserved activity against some metronidazole resistant bacteria Better compliance (Batina has once daily dosing as against three times daily dosing for Metronidazole; Batina also has a shorter duration of administration compared to Metronidazole)

Metronidazole, Secnidazole and Ornidazole all have alcoholic side chain & chances of Cross resistance is high among the three compared with Tinidazole which has entirely a different side chain (Ethyl Sulphonyl ethyl).

Batina is more cost effective in a general overview

A BRIEF COMPARISM OF BATINA VERSUS METRONIDAZOLE BATINA

METRONIDAZOLE

Gardiasis Adult: 2g (4 Tablets) Stat; repeat same dose after a week to achieve a higher clinical cure rate.

Children: 50 - 75mg / kg stat

Gardiasis Adult; 400mg tid x 5-7 days Children: 15mg / kg daily in three divided doses 7-10days

Intestinal Amoebiasis: Adult: 2g od for 2-3 days; therapy could be extended to 5days depending on the virulence of causative organsim.

Children: 50 - 75mg / kg od for 3days (for Hepatic amoebiasis increase to 5 days)

Adult; 400 - 800mg tid x 5-10 days Children: 35 - 50mg / kg daily in three divided doses

Trichomoniasis and B. Vaginosis Adult: 2g Stat; repeat same dose after a week to achieve a higher clinical cure rate Children: 50 - 75mg / kg stat. Repeat after dose after week

Adult; Tablet 400mg tid x 7days Children: 15mg / kg daily in 3 divided doses

Pelvic Inflammatory Disease 2g stat on day 1, then 1g od x 7days in conjuction with Zoixf (Ofloxacin) & Doxycycline + Fluconazole

400-800mg tid x 10-14days in conjuction with Zoixf and Doxycyline

Treatment of Anaerobic Infections Adult; Tablet: 2g stat on day, 1 then 1g od x 5days or more depending on severity of infection. Injection: 1.6g stat on day 1, then 800mg od x 5days.

Children: Half the adult dose or use 50-75mg / kg to calculate dose.

Intestinal Amoebiasis:

Trichomoniasis and B. Vaginosis

Pelvic Inflammatory Disease

Treatment of Anaerobic Infections Adult; Tablet 400 - 800mg tid x 7 - 14 days Injection: 200mg tid x 5 - 10days

Children: 15 - 30mg /kg daily in three divided dose

Prevention of Post - Operative Anaerobic bacterial Infections Adult 1.6g stat given as a single intravenous infection before surgery (or 800mg just before surgery and 800mg not later than 12 hours after surgery), then 800mg daily after 24 hrs for 3-5days; Children: half adult dose or use 50mg / kg once daily dosage.

Prevention of Post - Operative Anaerobic bacterial Infections 200mg iv infusion just before surgery and continued 8hourly for 5days or more, Children: 15mg / kg daily dose given in three divided doses

Necrotizing Gingivitis 2g stat for adult. Children 50mg / kg stat dose.

Repeat same dose after a week to achieve a higher clinical cure rate

Necrotizing Gingivitis 400mg tid x 5days for adults; Children 15 - 30mg/ kg daily in three divided doses.

OTHER INDICATIONS OF BATINA Treatment of ENT infections (e.g sore throat/tonsilitis which initially starts as aerobic bacterial infection but as it progresses it becomes mixed with anaerobic bacteria) 2g stat, then 1g od x 5days.

Bone infections e.g Osteomyelites, septic arthritis: 2g stat then 1g od x 10 - 14days. (or more depending on severity) Clostridium deficile diarrhoea due to ong term use of antibiotic: 2g stat, then 1g od x 3 - 5days.

PUD: 1g od or 500mg bd x 7days in conjuction with Omeprazole and Clarithromycin.

Intra - Cranial Infections e.g Subdural empyema, brain abcesses: 1.6g iv stat then 800mg od maintainance dose for up to two weeks depending on severity.

REFERENCES 1. Aldridge KE, Ashcraft D, Cambre K, Pierson CL, Jenkins SG , Roseblatt JE, Multicenter survey of the changing in vitro antimicrobial susceptibilities of clinical isolate of Bacteroides fragilis group, Prevotella, Fusobacterium, Porphyromonas, and Peptococus species.

Antimicrob Agents Chemothter 2001; 45:1238 - 1243 2. Hentges DJ. The anaerobic microflora of the human body. Clin infect Dis 1993; 164:S175 - 80 3. Brook, I. Microbiology and management of joint and bone infection s due anaerobic bacteria. J Orthop Sci. 2008; 13:160-9 4. Brook, I.; â&#x20AC;&#x2DC;Anaerobic Infections Diagnosis and managementâ&#x20AC;&#x2122;. A Textbook. Informa Healthcare USA, Inc. New York. 2007.

5. Brook, I. Microbiology and antimicrobial treatment of orbital and intracranial complications of sinusitis in children and their management.

Int J Pediator Otorhinolaryngol. 2009; 73:1183-6 6. JokpiA. Penetration of the blood brain carriers by metronidazole and tinidazole. Journal of antmicrobial chemotherapy, 1977.

Volume 3 (3):239-245.

Muller M. Reductive activation of nitromidazoles in anaerobic microorganisms. Biochem Pharmacol. 1986 Jan 1;35 (1):37-41.

Goldman P. The development of 5 - nitromidazoles for the treatment and prophylaxis of anaerobic bacteria infections J. Antimicrob Chemother. 1982 Aug; 10 SupplA :23-33.

Hentges DJ. The anaerobic microflora of the Human body. Clin infect Dis 1993; 164:S175-80.

Manes G, Balzano A. Tinidazole: from protozoa to Helicobacter pylori - the past , the present and future of a tinidazole with perculiarities.

Expert Rev Anti infection Ther. 2004 Oct; 2(5): 695 - 705.

Crowell AL, Sanders - Lewis KA, Sector WE. In vitro metronidazole and tinidzole activities against metronidazole - resistant strains of Trichomonas vaginalis. Antimicrob Agents Chemother. 2003 April; 47 (4): 1407-9.

Sobel JD, Nyirjesy P, Brown W. Tinidazole thraphy for metronidazole - resistant vagina Trichomoniasis. Clin infect Dis 2001 Oct 15;33(8); 1341-6. Epub 2001 Sep 17.

Manmen - Tobin A, Ailson JD. Management of metronidazole - resistant Trichomoniasis vaginalis - a new approach. Int JSTDAIDS. 2005 Jul; 16(7):488-90.

Nanda N, Michel RG, Kurdgelashvili G, Wende KA. Trichomoniasis and its treatment. Expert Rev Anti Infect Ther. 2006 Feb; 4(1):125-35 Martinidale, THE COMPLETE DRUG REFERENCE. 32Ed, Pg 594-1.

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