長女を2歳9ヶ月のときインドに連れて行った．多分に洩れず彼女も下痢になり，かなりひどかったので薬局で売薬を購入した．４０Rs（１００円）くらいだったかなあ．そのときの説明書があまりにも詳しくて，インドの底力を見たような気がしたのでここに再掲．
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Gramogyl Suspension
(Metronidazole Benzoate and Norfloxacin Oral Suspension)
For the use only of a Registered Medical Practitioner or a Hospital or Laboratory
COMPOSITION
Each 5 ml contains;
Metronidazole Benzoate I.P. equivalent to
Metronidazole 100 mg
Norfloxacin I.P. 100 mg
［ここにMetronidazoleとNorfloxacinの構造式が入る］
DESCRIPTION
Gramogyl is a fixed dose combination of Norfloxacin and Metronidazole.
Norfloxacin is a fluorinated carboxyquinolone antimicrobial agent with a broad spectrum of antibacterial activity. It is chemically designated as 1-ethyl-6-fluoro-1, 4-dehydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. The empirical formula for norfloxacin is C16H18FN3O3 and its molecular weight is 319.34.
Metronidazole is a nitroimidazole antibacterial agent with activity against intestinal protozoal pathogens and anaerobic bacteria. It is chemically designated as 2-(2-methyl-5-nitro-1H-imidazol-1-yl)-ethanol. The empirical formula for metronidazole is C6H9N3O3 and its molecular weight is 171.16.
PHARMACOLOGY
・Medical Rationale
Gramogyl is a rational combination which provides empirical therapy for diarrhoea or dysentery of protozoal, bacterial or mixed (protozoal and bacterial) origin as well as mixed anaerobic and aerobic infections viz. pelvic inflammatory disease.
［注：Gramogylは原生生物とバクテリアが原因である下痢や赤痢を経験的に（←ってすごい！）治癒する化合物］
The major bacterial pathogen in the etiopathogenesis of bloody diarrhoea is Shigella spp. The other common causes are Entamoeba histolytica and Giardia lamblia, both protozoa. Bloody diarrhoea can also be caused by entreoinvasive E.coli and Salmonella enteritidis. Bloody diarrhoea can often be due to mixed infections caused both by bacteria and protozoa (Entamoeba histolytica and Giardia lamblia). It has been reported that the virulence of E. histolytica increases in the presence of certain gram-negative bacteria. ［注：こんなところでグラム陰性細菌という表現にお目にかかるとは］The clinical presentation of bloody diarrhoea in the above diseases is very similar. Gramogyl combines antibacterial and antiprotozoal actions and provides empirical therapy for gastointestinal tract infections such as diarrhoea or dysentery of protozoal, bacterial or mixed origin.
・Mode of Action
［注：治る仕組みを科学的に解説！！］
Fluoroquinolones, including norfloxacin, bring about their bactericidal action by inhibiting the bacterial topoisomerase II (DNA gyrase) enzyme. Topoisomerases are responsible for continuous introduction of negative supercoils into DNA.This is an ATP dependent reaction that requires both strands of the DNA to be cut to permit passage of a segment of DNA through the break; the break is then resealed. ［注：トポイソメラーゼやネガティブスーパーコイルって日本の市販薬の説明書には絶対出てこない！］Fluoroquinolones decrease the introduction of negative supercoils into DNA and cause rapid cessation of DNA synthesis by interfering with the propagation of DNA replication.［注：微生物のDNA合成を妨げる］
Metronidazole exerts anti microbial action in an anaerobic environment by the following possible mechanism: once metronidazole enters the organism, the drug is reduced by intracellular electron transport proteins. .［注：Metronidazoleが微生物内に入ると，微生物の細胞内の電子伝達系に関与する蛋白に還元される］Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in tern, react with cellular components resulting in death of the microorganism.［注：濃度勾配が維持されて，フリーラジカルの生成がおこると推測され，微生物を死滅させる］
・Antibacterial Spectrum
Norfloxacin is active in vitro against most gram-negative viz. Enterobacteriaceae including Shigella species, Salmonella species, Citrobacter, and Vibrio species, Escherichia coli, Klebsiella species, Pseudomonas aeruginosa including gentamicin resistant strains, and Yersinia enterocolitica. Norfloxacin is also active against penicillin-resistant strains of Neisseria gonorrhoeae and beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. Among gram positive pathogens streptcocci are moderately susceptive in vitro to norfloxacin.［注：上記はNorfloxacinが対象とする微生物．どれも腸内にいる］
Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess any clinically relevant activity against facultative anaerobes and aerobes. Against susceptive organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to have in vitro clinical activity against the following organisms;
• Anaerobic gram-negative bacilli, including Bacteroides species including Bacteroides flagillis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus) Fusobacterium species.
• Anaerobic gram-positive bacilli, including Clostridium species and susceptible stains of Eubacterium
• Anaerobic gram-positive cocci, including Peptococcus species, Peptostreptcoccus species
［注：Metronidazoleが対象とする微生物はバチルスなどの嫌気性細菌］
・Pharmacokinetics
［注：薬物動態も日本の説明書にはない．体内でどのくらいが未反応のまま残るのか，半減期はいくらか，など］
Norfloxacin is rapidly absorbed after oral administration. A single oral dose of 400 mg produces a peak plasma concentration of 1.5 mcg/ml achieved 1-2 hours after administration. Norfloxacin is bound to plasma proteins up to an extent of 14 %. It is widely distributed, and high concentrations are achieved in bile. Norfloxacin is partially metabolised in the liver. It is eliminated through metabolism, biliary excretion, and renal excretion. About 30% is eliminated unchanged in urine. The plasma elimination half-life of norfloxacin is 4 hours. Norfloxacin is primarily eliminated by renal excretion (both glomerular filteration and tubular excretion), therefore plasma clearance of norfloxacin is decreased in patients with impaired renal function.
Following oral administration metronidazole is well absorbed and peak plasma concentration attained between one and two hours.
Average elimination half-life in healthy human is 8 hours. Plasma concentrations are proportional to the adminstered dose. Metronidazole is primarily metabolised by side-chain oxidation and glucuronide conjugation. Approximately 20 % of the total metronidazole remain unchanged. Metronidazole is the major component appearing in plasma, with lesser quantities of the metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. The major route of elimination of metronidazole and its metabolites is via the urine (60 to 80% of the dose), with fecal excretion accounting for 6to 15% of the dose. Renal clearance of metronidazole is approximately 10 ml/min/1.73m2. Decreased renal function dose not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.
INDICATIONS
DOSAGE AND ADMINISTRATION
用量と用法（略）
PRECAUSIONS
安全上のご注意［注：この辺は日本の売薬にも書いてあるが、日本のよりずっと詳しい］
・General
・Warnings
・Contraindications
・Pregnancy
・Lactation
・Paediatrics
・Geriatrics
・Carcinogenicity / Mutagenicity / Impairment of Fertility
・Drug Interactions
・Laboratory Value Alterations
・Adverse effects
OVERDOSAGE
STORAGE
REFERENCES（略）
