paromomycin Property

alpha 

D25 +65 ±3°

Boiling point:

658.93°C (rough estimate)

Density 

1.3753 (rough estimate)

refractive index 

1.7500 (estimate)

solubility 

Methanol (Slightly), Water (Slightly)

form 

Solid

pka

12.93±0.70(Predicted)

color 

Off-White to Pale Beige

Stability:

Hygroscopic

Safety

Toxicity

LD50 in rats, mice (mg/kg): >1625, >2275 orally; >650, 423 s.c.; 156, 90 i.v. (Coffey)

Hazard and Precautionary Statements (GHS)

paromomycin Chemical Properties,Usage,Production

Description

Paromomycin is recommended for treatment of acute and chronic forms of intestinal amobiasis, as well as for treating intestinal bacteria Salmonella and Shigella. Synonyms of this drug are aminosidine, catenulin, crestomycin, hydroxymycin, monomycin, zygomycyn, and others.

Originator

Humatin,Parke Davis ,US,1960

Uses

Paromomycin Deuterated Acetic Acid Salt is the isotope labelled analog of Paromomycin Sulfate. Paromomycin Sulfate is an aminogycoside antibiotic designed to fight intestinal infections such as cryptosporidiosis, amoebiasis, and leishmaniasis. Its antiprotozoal activity makes it an effecive histomonostatic feed additive in turkey poults experimentally infected with Histomonas meleagridis.

Definition

ChEBI: Paromomycin is an amino cyclitol glycoside that is the 1-O-(2-amino-2-deoxy-alpha-D-glucopyranoside) and the 3-O-(2,6-diamino-2,6-dideoxy-beta-L-idopyranosyl)-beta-D-ribofuranoside of 4,6-diamino-2,3-dihydroxycyclohexane (the 1R,2R,3S,4R,6S diastereoisomer). It is obtained from various Streptomyces species. A broad-spectrum antibiotic, it is used (generally as the sulfate salt) for the treatment of acute and chronic intestinal protozoal infections, but is not effective for extraintestinal protozoal infections. It is also used as a therapeutic against visceral leishmaniasis. It has a role as an antibacterial drug, an antiprotozoal drug, an anthelminthic drug and an antiparasitic agent. It is an aminoglycoside antibiotic and an amino cyclitol glycoside. It is functionally related to a streptamine.

Indications

The antibacterial activity and indications for using paromomycin are analogous to those of neomycin. In addition, it is recommended for treating severe and chronic forms of gastric amebiasis. Synonyms of this drug are aminosidine, catenulin, crestomycin, hydroxymycin, monomycin, zygomycyn, and others.

Manufacturing Process

As described in US Patent 2,916,485: 12 liters of a nutrient medium having the following composition is placed in a 30 liter fermenter equipped with stainless steel fittings including sparger, impeller, baffles and sampling lines and the medium is sterilized by heating at 121°C for two hours.
The medium is cooled and inoculated with 20 ml of a suspension of the spores from two Mover's sporulation agar slant cultures of Streptomyces rimosus forma paromomycinus in sterile 0.1% sodium heptadecyl sulfate solution. The inoculated culture mixture is incubated at 26°C for sixty hours during which time the mixture is stirred at 200 rpm and sterile air is passed into the medium through the sparger at the rate of 12 liters per minute. A portion of the resulting incubated culture mixture is employed for inoculation of 16 liters of a nutrient medium having the following composition:
The pH of the latter nutrient medium is adjusted to 7.5 with 10 N sodium hydroxide solution and is placed in a 30 liter glass fermenter equipped withsparger, impeller, baffles and sampling line, The medium is sterilized by heating at 121°C for two hours, is allowed to cool and is then inoculated with 800 ml of the culture mixture obtained as described above.
The resulting culture mixture is incubated at 26°C for 94 hours during which time the mixture is stirred at 200 rpm and sterile air is passed into the medium through the sparger at the rate of 16 liters per minute. During the incubation, foaming is avoided by the addition, as needed, of crude lard and mineral oils containing mono-and diglycerides.
At the end of the incubation period the fermentation culture mixture is adjusted to pH 2 with concentrated hydrochloric acid, the solid material present is removed by filtration, and the filter cake is washed with water. The washings are combined with the main filtrate, adjusted to pH 7.0; and 15.5 liters of the filtered culture liquid is introduced into a columnar exchanger (1.5'' i.d.) packed with 380 ml of carboxylic acid resin which has been preliminarily washed in succession with two liters of an aqueous solution of 37.5 grams of sodium hydroxide and with two liters of water. The column containing paromomycin is washed with two hold-up volumes of water and is eluted with 0.5 N hydrochloric acid.
The first 19.4 liters of percolate contains little or no paromomycin and varies in pH from 6 to 7.3. When the pH of the eluate begins to fall below 6.0, two liters of the eluate are collected.
The two liter portion of the eluate, collected as indicated, is neutralized to pH 6 with 10 N sodium hydroxide solution and is filtered. The filtrate is concentrated by evaporation in vacuo to a volume of approximately one liter
An adsorption column is prepared by pouring a slurried aqueous mixture of 65 grams of acid-washed activated charcoal (Darco G-60) and 50 grams of diatomaceous earth in a 1.5'' column and 300 ml of the concentrated filtrate is added. The column is washed with 400 ml of water and eluted successively with 325 ml of water, 425 mi of 1% aqueous acetone and 400 ml of 10% aqueous acetone. The water and acetone eluates are concentrated and lyophilized to give paromomycin hydrochloride as a powder. The product is purified by taking up the powder in methanol, adding a large excess of acetone to the solution, recovering the precipitate which forms by filtration. The product, paromomycin hydrochloride, has an optical rotation [α]D25 = +56.5° (1% in water). By analysis it contains 35.71% carbon, 6.95% hydrogen, 8.24% nitrogen and 21.5% chlorine.
In order to obtain paromomycin in free base form, the hydrochloride is dissolved in water as a 3% solution, the solution is poured into an adsorption column containing an anion exchange resin (Amberlite IR-45 or preferably IRA-411 or IRA-400) in the hydroxyl form and the column is washed with a small amount of water.
The aqueous percolate is concentrated to dryness by lyophilization, and the solid product obtained is purified by taking up in boiling absolute ethanol, cooling and recovering the solid product paromomycin; [α]D25 = +64° (1% in water). By analysis it contains 45.17% carbon, 7.44% hydrogen and 10.35% nitrogen.

brand name

Gabbroral;Humagel;Humatin;Sinosid.

Therapeutic Function

Amebicidal

World Health Organization (WHO)

Paromomycin, an aminoglycoside antibiotic was introduced into medicine in 1959 for the treatment of protozoal, helminthic and bacterial infections. It has been associated, particularly when used by parenteral route, with severe adverse effects including renal damage, neuromuscular blockage and ototoxicity, possibly leading to deafness in some patients. This route of administration is now considered obsolete. However, parenteral dosage forms of paromomycin may still remain available in certain countries.

Antimicrobial activity

A fermentation product of Streptomyces rimosus var. paromomycinus, supplied as the sulfate. The commercial product is a mixture of the two isomeric paromomycins I and II, which are closely related to neomycin.
The antibacterial activity is almost identical to that of neomycin. Since it differs from neomycin in having a hydroxyl rather than an amino group at the 6′-position it is not sensitive to AAC(6′) modifying enzymes. It is active against M. tuberculosis, including multidrug-resistant strains, and the M. avium complex.
Unlike other aminoglycosides, paromomycin is active against some protozoa, including Entamoeba histolytica, Cryptosporidium parvum, Leishmania spp., Giardia lamblia and Trichomonas vaginalis. It also exhibits activity against the tapeworms Taenia saginata, Taenia solium, Diphyllobothrium latum and Hymenolepis nana.
It closely resembles neomycin in pharmacokinetic behavior and liability to produce deafness and intestinal malabsorption.

Clinical Use

Intestinal amebiasis (oral)
Cutaneous leishmaniasis (topical) and visceral leishmaniasis (intramuscular)
Nitroimidazole-resistant trichomoniasis (topical)
Its antiprotozoal activity has attracted some attention, but it has largely been superseded by more active and less toxic compounds. Success in treating nitroimidazole-resistant trichomoniasis with topical paromomycin has been reported. Trials in India and East Africa of parenteral paromomycin alone, or in combination with sodium stibogluconate, for treatment of visceral leishmaniasis have shown promising results.

Synthesis

From a chemical point of view, paromomycin, O-2-amino-2-deoxy-α- D-glucopyranosyl(1→4)-O-[O-2,6-diamino-2,6-dideoxy-β-L-idopyranoxyl-(1→3)-β-Dribofuranosyl-(1→5)]-2-deoxy-D-streptamine (32.4.5), differs from neomycin B only in the replacement of the 6-amino group in the glucopyranosyl region of the molecule with a hydroxyl group, and it is isolated from a culture fluid of the actinomycete S. rimosus.

Veterinary Drugs and Treatments

Paromomycin may be useful as a secondary treatment for cryptosporidiosis in dogs and cats. It has also been used topically to treat cutaneous Leishmaniasis. In humans, it has been used as an alternative treatment for giardiasis, Dientamoeba fragilis, and hepatic coma.