Oral activity, drugs

Miltefosin The antileishmanial activity of this anticancer drug was discovered in the mid-1980s. It is the first oral drug available to treat visceral and cutaneous/mucocutaeous leishmaniasis. However, the registration process is slow. 

Because of the possibility of an antacid interfering with the activity of other oral drugs no oral drug should be administered within 1 to 2 hours of an antacid. 

Kelder et al. [19] have shown that PSA can be used to model oral absorption and brain penetration of drugs that are transported by the transcellular route. A good correlation was found between brain penetration and PSA (n=45, r=0.917). From analyzing a set of 2366 central nervous system (CNS) and non-CNS oral drugs that have reached at least phase 11 clinical trials it was concluded that orally active drugs that are transported passively by the transcellular route should have PSA< 120 Al In addition, different PSA distributions were found for CNS and non-CNS drugs. 

Estramustine, an oral drug, also inhibits microtubule assembly and has weak estrogenic activity at the estradiol hormone receptors of the cell. Approximately 75% of a dose of estramustine is absorbed.15 The terminal half-life ranges between 20 to 24 hours, with nonrenal excretion as the major route of elimination. This drug is used primarily for the treatment of prostate cancer, but its use is limited by the side effects, which include nausea and vomiting, diarrhea, thromboembolic events, and gynecomastia. 

Hydroxyurea is an oral drug that inhibits ribonucleotide reductase, which converts ribonucleotides into the deoxyribuon-cleotides used in DNA synthesis and repair. The time to peak concentrations of hydroxyurea is 1 to 2 hours after oral administration. Approximately 50% is degraded by the liver to form urea and respiratory carbon dioxide. The remainder is excreted by the kidney. The half-life ranges from 3.5 to 4.5 hours. Hydroxyurea has shown clinical activity in the treatment of chronic myelocytic leukemia, polycythemia vera, and thrombocytosis. The major side effects are myelo-suppression, nausea and vomiting, diarrhea, and constipation. Rash, mucositis, and renal tubular dysfunction occur rarely. 

Clearly the physicochemical properties of a drug are a decisive factor in its overall activity. Where possible, molecular structures should be optimized to obtain best clinical performance. Rarely does an oral drug have physicochemical features suitable for topical or transdermal therapy, and it can take a great deal of systematic research to identify where the best balance of activity and permeability lies. Experience with corticosteroids suggests that as much as a 100-fold improvement in clinical activity may be attainable through molecular design, for today s most potent topical corticosteroids are more active than hydrocortisone by a factor at least this large. 

Several attempts have been made to estimate the dose required in humans in relation to a drug s potency, and to put this into the context of solubility and permeability for an optimal oral drug [2, 3]. A relatively simple example of this is where a 1.0 mg kg-1 dose is required in humans, then 52 pg mL"1 solubility is needed if the permeability is intermediate (20-80%) [3]. This solubility corresponds approximately to 100 pM of a compound with a MW of 400 g mol-1. Most screening activities for permeability determinations in, e.g., Caco-2, are made at a concentration of 10 pM or lower due to solubility restrictions. The first implication of this is that the required potency for these compounds needs to correspond to a dose of <0.1 mg kg-1 in humans if the drug should be considered orally active. Another implication would be the influence of carrier-mediated transport (uptake or efflux), which is more evident at low concentrations. This could result in low permeability coefficients for compounds interacting with efflux transporters at the intestinal membrane and which could either be saturated or of no clinical relevance at higher concentrations or doses. 

Complex 11 (JM216) is currently in phase II clinical trials as an oral drug. It is reported to have superior in vitro and in vivo activity... 

Martin YC, Kofron JL, Traphagen LM. (2002) Do structurally similar molecules have similar biological activity /. Med. Chem. 45 4350-4358. Lajiness MS, Vieth M, Erickson J. (2004) Molecular properties that influence oral drug-like behavior. Curr. Opin. Drug Discov. Devel. 7 470-477. 

In vivo assays were performed using the standard Peters 4-day test. Ihe activity refers to oral antimalarial activity and reflects the concentration of drug required to reduce parasitaemia, in mice infected with Plasmodium berghei, by 50% of the control. 

In RA the disease-activity dependent degree of erosion and IMNs naivety or non-naivety determine the achievement of Remission with Oral Drugs (RworalDs) and Remission without Drug (RwD). SBC-5-IMNs uses for endpoints the ACR Remission Criteria Plus. 

NSAID-refractory-AS is defined when after treatment with at least 2 different NS AID over a period of at least 2 months, ASAS 20 is not obtained, and ESR, CRP, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score do not improve, or worsens versus baseline. Indications for therapy with SBC-5-IMNs are in NSAID-refractory AS with ESR > 40 mm and a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > 4. Less than 5% of patients with NSAID-refractory AS in the community at large fulfill these conditions. Remission is defined when ESR and VAS have declined to <10 mm (men <5 mm) and the disease activity scores are <1 (scale 0-10). Remission with oral drugs is defined when remission is maintained with oral drugs for at least 2 years. Remission without drugs is defined when remission without drugs is sustained without relapse for at least 2 years. 

Extensive enterohepatic cycling may be partly responsible for a drug s long persistence in the body. Orally administered activated charcoal and/or anion exchange resins have been used clinically to interrupt enterohepatic cycling and trap drugs in the gastrointestinal tract. 

Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension, and drugs activating receptors can be used for this purpose. Midodrine, an orally active 04 agonist, is frequently used for this indication. Other sympathomimetics, such as oral ephedrine or phenylephrine, can be tried. 

The dosage for urinary tract infection in adults is 100 mg orally taken four times daily. The drug should not be used to treat upper urinary tract infection. Oral nitrofurantoin can be given for months for the suppression of chronic urinary tract infection. It is desirable to keep urinary pH below 5.5, which greatly enhances drug activity. A single daily dose of nitrofurantoin, 100 mg, can prevent recurrent urinary tract infections in some women. 

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