Oral administration

This is usually done by gavage, (direct intubation into the stomach) or by administration of encapsulated material. This allows accurate measurement of the amount administered and an accurate time of administraton. It is not usually done by mixing with the feed or drinking water, as the material would frequently not be acceptable to the animal and the amount consiuned would not be known. This method of administration omits one area of exposure which is important in human accidental exposure, emd that is absorption in the mouth or buccal area however, there is no reasonable way to overcome this. 

As previously mentioned, inhalation toxicity is reported as an LC50, the lethal concentration. Obviously the toxic effects of inhaled materials are related to the weight of the material inhaled in relation to the body weight of the animal and, on occasion, it may be desirable to estimate this niunber. This can be done using the formula below  

In the study of chemical mutagenesis, special techniques are required for the administration of chemicals in accordance with their toxicity, permeability, metabolic characteristics, and other properties. The procedures so far utilized are oral administration, injection into the hemocoele, soaking of eggs, and gas treatment. 

By oral administration, a positive mutagenic response has been obtained for and Panfuran (3-amino-6-2-(5-nitro-2-furyl) vinyl—1,2,4-triazine hydrochloride, NFT). The chemicals were given to larvae just after the second molt by painting on mulberry leaves. 

Administration of chemical compounds by injection is unnatural, but has been conveniently practiced in several experiments. Chemicals are dissolved in physiological saline or 0.85% aqueous saline solution, and these are injected into the hemoceole. Compounds insoluble or hardly soluble in water are 

This table presents the number of whole and mosaic mutants detected at and -floci the induced mutation frequencies are calculated by subtracting the control frequencies. It can be noted from the table that mutation frequencies calculated on a per microgram per locus basis vary according to the administered dose even in a group injected at the same stage. Treatment with higher doses often resulted in reduced efficiency in inducing mutations. 

The mutagenic response is highest in late spermatids at an early pupal stage. It is low in the larval stage and increases rapidly after the mature larva 

Multiple emulsions have also been proposed for the oral delivery of proteins. Because of the relatively large quantities of insulin historically available and the well-known interest in alternative insulin delivery systems (see Chapter 13), the incorporation of insulin within W/OAV multiple emulsions for oral administration has served as the model system (Engel et al, 1968 Shichiri et al, 1974). Engel et al (1968) reported on the in-traduodenal administration of insulin multiple emulsions to Wistar rats 

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The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

Ketoconazole. Initial observations indicating that oral administration of ketocona2ole (10) produced good results in seborrheic ec2ema and dandruff, led to the development of a 2% cream and a 2% shampoo (scalp gel) of this antimycotic (17,18). Naturally, these two topical forms of ketocona2ole [65277-42-1] are highly active against superficial mycoses. 

Toxicological studies conducted on DCPD indicate that it is a moderately toxic material and, to some extent, an irritant and a narcotic. By oral administration in the rat, the LD q is 0.82 g/kg of body weight, and by skin absorption in the rabbit, the LD q is 6.72 ml,/kg. An atmospheric concentration of 2000 ppm causes death in rats exposed for a period of 4 hours. 

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

Eventually, the proposed method was successfully applied to quantify clarithromycin in spiked human plasma and real samples from healthy volunteers after oral administration of the dmg indicating the utility of this method for clinical and bioavailability studies. 

Polymeric ethyl cyanoacrylate exhibits very low toxicity properties. In tests with laboratory rats, oral administration of 6400 mg/kg of the polymer failed to harm the test animals. Some skin irritation did occur in tests on guinea pigs, but skin sensitization or absorption through the skin was not observed [45]. 

Acute Toxicity The adverse effect occurring within a short time of (oral) administration of a single dose of a substance or multiple doses given within 24 hours. 

Acylation of a sulfonamide on the amide nitrogen serves to remove the sometimes objectionable taste of these drugs. Reac-I ion of intermediate, 154, with acetic anhydride followed by reduction of the nitro group affords acetyl methoxyprazine (156). The last, which has much the same biologic action as Mie parent compound, is used for oral administration in syrups. 

Although both estrone and estradiol are available for replacement therapy, they suffer the disadvantage of poor activity on oral administration and short duration of action even when administered parenterally, because of ready metabolic disposition. In order to overcome these deficiencies, there was developed a series of esters of estradiol with long-chain fatty acids. These esters are oil-soluble and correspondingly water-insoluble compounds. 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Figure 11.4 Chromatograms of plasma samples on a silica-chiralcel OJ coupled column system (a) plasma spiked with oxprenolol (internal standard) (b) plasma spiked with 040 p-g/ml metyrapone and 0.39 p-g/ml metyrapol (racemate) (c) plasma sample obtained after oral administration of 750 mg metaiypone. Peaks are as follows 1, metyrapone 2, metyrapol enantiomers 3, oxprenolol. Reprinted from Journal of Chromatography, 665, J. A. Chiarotto and I. W. Wainer, Determination of metyrapone and the enantiomers of its chfral metabolite metyrapol in human plasma and urine using coupled achfral-chfral liquid cltro-matography, pp. 147-154, copyright 1995, with permission from Elsevier Science.

It has a water solubility of about 55%. It may ba compounded in the form of tablets, for oral administration, or may be prepared in solution for distribution in ampoules. For tha manufacture of solutions for packaging in ampoules. It is more convenient to simply dissolve tha theophylline and tha butanol amine in water, without going through the intermediate step of separating the crystalline salt. 

FIGURE 8.25 Repeated oral administration of drags leads to steady-state plasma concentrations. If elimination is rapid and administration not often enough, then an elevated and therapeutically effective steady-state concentration may not be achieved (green lines). In contrast, if elimination is very slow (or administration too often), then an accumulation of the drag may be observed with no constant steady state (red line). Bine line shows a correct balance between frequency of administration and elimination. 

The immobilization of enzymes with the formation of insoluble forms is usually intended for the development of specific catalysts for technical purposes. Here, we consider another medico-biological problem of the preparation of insoluble enzymatic systems based on crosslinked polyelectrolytes, used in the replacement therapy for oral administration. 

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