RU2194506C2 - Combination of inhibitors of hiv-protease - Google Patents

Abstract

FIELD: medicine, virology. SUBSTANCE: invention relates to method involving administration in needing patient the compound N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(tert. -butylcarbamoyl)-piperazinyl))pentane-amide (component A) or its pharmaceutically acceptable alt in combination with (component B) or its pharmaceutically acceptable salt. The proposed method ensures to enhanced effectiveness of treatment due to adverse effects. Invention can be used for inhibition of activity of HIV-proteases, prophylaxis and treatment of HIV-infection or treatment of patients with AIDS. EFFECT: enhanced effectiveness of treatment. 7 cl, 4 tbl

Description

 The application is a partial continuation of the application Merck 19280, US registration number (U.S.S.N.) 08/289474, filed August 11, 1994.

 This application relates to application Merck 18996, (U.S.S.N.) 08/059038, filed May 7, 1993, and 189961 A, (U.S.S.N.) 08/235576, filed April 29, 1994.

 A retrovirus, called the human immune deficiency virus (HIV), is the causative agent of a complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and destruction of the central and peripheral nervous systems. This virus was formerly known as LAV (lymphadenopathic virus), HTLV-111 (human T-lymphocytic virus), or ARV. A common sign of retroviral replication is the extensive post-translational processing of polyprotein precursors encoded by a viral protease with the generation of mature viral proteins necessary for the assembly of the virus and its function. Inhibition of this processing prevents the formation of a normally infectious virus. For example, Kohl, N.E., et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) showed that genetic inactivation of an HIV-encoded protease results in the production of particles of an immature, non-infectious virus. These results indicate that inhibition of HIV protease is a feasible method of treating AIDS and preventing or treating HIV infection.

 HIV nucleic acid sequencing shows the presence of the pol gene in one open reading frame / Ratner, L., et al., Nature, 313, 277 (1985) /. The homology of the amino acid sequence clearly shows that the col sequence encodes reverse transcriptase, endonuclease and HIV protease / Toh, et al., EMBO J. 4, 1267 (1985); Power, M. D., et al., Science, 231, 1567 (1986); Pearl, L. H., et al., Nature, 329, 351 (1987).

Называемое N-(2(R)-гидрокси-1(S)-инданил)-2(R)-фенилметил-4(S)-гидрокси-5-(1-(4-(3-пиридилметил)-2(S)-N'-(трет-бутилкарбамоил)пиперазинил)пентанамид или его фармацевтически приемлемая соль является мощным ингибитором ВИЧ-протеазы и полезным при лечении СПИДа или ARC без существенного побочного действия или токсичности.Compound I of the formula

Called N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4 (S) -hydroxy-5- (1- (4- (3-pyridylmethyl) -2 (S ) -N '- (tert-butylcarbamoyl) piperazinyl) pentanamide or a pharmaceutically acceptable salt thereof is a potent HIV protease inhibitor and useful in the treatment of AIDS or ARC without significant side effects or toxicity.

 Applicants have found that the administration of compound I in combination with other HIV protease inhibitors is suitable for the treatment of AIDS or ARC (AIDS-associated complex).

 Applicants show that the combination of compounds of the present invention is an effective HIV protease inhibitor.

 In the present invention, Applicants administer a potent HIV protease inhibitor, compound I, either simultaneously or alternately with one or more other HIV protease inhibitors, such as compounds I, II, III or IV.

Summary of the invention
The combination of the present invention is suitable for inhibiting HIV protease, preventing HIV infection, treating HIV infection and treating AIDS and / or ARC, in the form of compounds, pharmaceutically acceptable salts (as appropriate), ingredients of the pharmaceutical composition, alone or in combination with other antiviral agents, anti-infectious agents, immunomodulators, antibiotics or vaccines. Also described are methods of treating AIDS, methods of preventing HIV infection and methods of treating HIV infection.

Detailed Description of the Invention and Preferred Embodiments
The present invention relates to the combination of certain compounds, or pharmaceutically acceptable salts thereof, for inhibiting HIV protease, preventing or treating HIV infection, and for treating the resulting acquired immunodeficiency syndrome (AIDS). This combination is defined as follows:
a combination comprising compound I and an HIV protease inhibitor selected from compounds I, II, III or IV.

 An HIV protease inhibitor, compound I, is synthesized according to the scheme of the application Merck 18597 Y, EP 0541168, published May 12, 1993, incorporated herein by reference. Compound L-735524 is N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4- (S) -hydroxy-5- (1- (4- (3- pyridylmethyl) -2 (S) -N '- (tert-butylcarboxamido) piperazinyl) pentanamide or a pharmaceutically acceptable salt thereof.

или его фармацевтически приемлемую соль. Его синтезируют по методике, описанной в ЕР 0346847. См. также R.A.Roberts et al., Science, 248, 358 (199).Compound 1 is a compound of the formula

or a pharmaceutically acceptable salt thereof. It is synthesized according to the procedure described in EP 0346847. See also RARoberts et al., Science, 248, 358 (199).

Его синтезируют по методике ЕР 0346847, РСТ WO 92/08700 и РСТ WO 92/8698.Compound II is a compound of the formula

It is synthesized according to the method of EP 0346847, PCT WO 92/08700 and PCT WO 92/8698.

или его фармацевтически приемлемую соль. Его синтезируют по методам ЕР 0486948 и РСТ WO 94/14436.Compound III is a compound of the formula

or a pharmaceutically acceptable salt thereof. It is synthesized according to the methods of EP 0486948 and PCT WO 94/14436.

или его фармацевтически приемлемые соли. Его синтезируют по методам WO 95/09843.Compound IV is a compound of the formula

or its pharmaceutically acceptable salts. It is synthesized according to the methods of WO 95/09843.

 The pharmaceutically acceptable salts of the present invention (in the form of water- or oil-soluble or dispersible products) include the usual non-toxic salts or salts of Quaternary ammonium bases, which are formed, for example, inorganic or organic acids or bases. Examples of such acid addition salts are acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphorites, camphorsulfonates, cyclopentane propionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoate, glucoheptanoate heptanoate hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, oxalates, pamoates, pectins, persulfates, 3-phenylpropionates, picrates, pivalate s, propionates, succinates, tartrates, thiocyanates, tosylates and undecanoates. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and amino acid salts, such as arginine, lysine and so on. Also, basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Other pharmaceutically acceptable salts are ethanolate sulfates and sulfates.

Where appropriate, C _1-4 alkyl esters as prodrugs are included.

 The combination of the compounds of the present invention is useful in inhibiting HIV protease, preventing or treating infection with human immunodeficiency virus (HIV), and in treating pathological conditions resulting from infection, such as AIDS. Treating AIDS or preventing or treating HIV infection is defined as including, but not limited to, the options for treating a variety of HIV conditions: AIDS, ARC (AIDS-related complex), both symptomatic and asymptomatic, and the actual or potential exposure to HIV. For example, the compounds of the present invention are useful in treating HIV infection in cases of suspected past exposure to HIV, for example, blood transfusion, replacement of body water, a traumatic injection, or exposure to a patient’s blood during surgery.

 Combinations of the present invention are also useful in the preparation and screening of antiviral compounds. For example, the combinations of the present invention are useful for isolating enzyme mutants, which are excellent screening tools for the analysis of potent antiviral compounds. In addition, the compounds of the present invention are useful in establishing or determining the binding site of other antiviral agents to an HIV protease, for example, through competitive inhibition. Therefore, the combinations of the present invention are commercial products that are sold for these purposes.

 Combinations of the present invention, for the aforementioned purposes, can be administered orally, parenterally (including subcutaneous injection, intravenous, intramuscular, intrathoracic injection or infusion method), by inhalation by spray or rectally, in unit dose formulations containing the usual non-toxic pharmaceutically acceptable carriers, adjuvants and excipients .

 Thus, the present invention also relates to a method of treatment and a pharmaceutical composition for treating HIV infection and AIDS. The treatment consists in administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of each compound in the combination of the present invention.

 These pharmaceutical compositions may exist in the form of orally administered suspensions or tablets; nasal aerosols; sterile injectable preparations, for example, as sterile injectable aqueous preparations or oily suspensions or suppositories.

 When the compositions are administered orally in the form of suspensions, such compositions are prepared by methods well known in the art of pharmaceutical preparation, and they may contain microcrystalline cellulose to give volume, alginic acid or sodium alginate as a suspending agent, methyl cellulose as a thickening agent, and known in the technique of sweeteners and flavoring agents. The immediate release drug tablet compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose, and / or other excipients, binders, fillers, disintegrants, diluents and lubricants known in the art.

 When the compositions are administered by nasal aerosol or inhalation, such compositions are prepared according to methods well known in the art of pharmaceutical preparation, and they can be prepared as solutions in physiological saline, using benzyl alcohol or other suitable preservatives, absorption promoters, for enhancing the bioavailability of fluorocarbons and / or other solubilizing or dispersing substances known in the art.

 Injectable solutions or suspensions may be prepared by methods known in the art using non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersants or wetting agents and suspending agents, such as sterile soothing fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

 When the compositions are administered reactively in the form of suppositories, such compositions can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures but dilute and / or dissolve in the rectal cavity with release medicinal product.

 The compounds of the present invention can be administered to humans in a dosage range specific for each compound. The compound or its pharmaceutically acceptable salt is administered orally at a dosage range of from 40 mg to 4000 mg per day, once or separately up to 4 times per day. A preferred oral dosage range for compound I or a pharmaceutically acceptable salt thereof is from 200 mg to 1000 mg administered three times a day. Compound 1 or a pharmaceutically acceptable salt thereof is administered orally at a dosage range of 100 mg to 4000 mg per day. A preferred oral dosage range is from 200 mg to 1000 mg when administered 3 times a day. Compound 11 is administered orally, for example, as an elixir in 30% aqueous ethanol, with a dosage range of 100 mg to 4000 mg per day. A preferred oral dosage range for compound 11 is from 200 mg to 1000 mg when administered 3 times per day. Compound III or a pharmaceutically acceptable salt thereof is administered orally at a dosage range of 100 mg to 4000 mg per day. A preferred oral dosage range for compound III or a pharmaceutically acceptable salt thereof is from 200 mg to 1000 mg when administered 3 times per day. Compound IV or a pharmaceutically acceptable salt thereof is administered orally at a dosage range of 100 mg to 4000 mg per day. It should be borne in mind, however, that the specific dose level and frequency of administration for a particular patient may vary and will depend on many factors, including the activity of the particular compound used, metabolic stability and duration of action of this compound, age, body weight, general condition health, gender of the patient, nutrition, method and time of administration, rate of excretion, combination of drugs, severity of a particular condition and recipient receiving treatment.

EXAMPLE 1
Protocol pharmacokinetic evaluation of treatment with combination only with compound 1
This is a cross-sectional protocol for multidose three-phase treatment of randomly selected HIV-infected patients to evaluate the pharmacokinetics and safety of co-administration of compound I and compound 1.

 Twelve randomly selected HIV-infected patients receive three different treatments, consisting of dosing for a full seven days and one additional dose of active compound I and compound 1 placebo (treatment A), placebo compound I and compound 1 (treatment B) and active compound I and active compound 1 (treatment B). These treatments are described in Table 1 (see end of description).

 Compound I is taken as three 200 mg capsules and compound 1 as three 200 mg capsules. Placebo capsules correspond to both active compound I and active compound 1.

 Compound I or an appropriate placebo is taken every eight hours. Potential subjects are assessed by accepting a complete medical history, objective examination (including vital signs with orthostatic indicators), 12-lead ECGs, and laboratory tests (including determining CD4 counts) for approximately one month from the start of the study.

 For safety analysis, blood and urine are taken during each treatment period for laboratory safety tests and a physical examination is performed before the first dose (day 1) and on the day of the last dose (day 8) of each treatment period. Additionally, an ECG with 12 leads is taken before and after 1 hour after the first dose, as well as 1 hour after the last dose of each treatment period. Indicators of vital functions, including orthostatic indicators, are usually measured on a schedule on the first and last days of doses. Patients are given one day during the week of taking the medicine (the same day of taking the medicine for each treatment for an individual patient - 3, 4 or 5 days) for taking the medicine under supervision, monitoring side effects and monitoring vital signs. Patients have daily observation cards to record the time of taking all doses of the drug and notes on any adverse manifestations during each treatment period. A safety assessment after the end of the regimen, consisting of laboratory tests for safety, an objective examination and an ECG, is performed 24 hours after the last treatment.

 During treatment A, B and C, blood samples are taken to determine the plasma content of compound I and compound 1 through 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the last dose (day 8). The pharmacokinetic parameters that are tested include the maximum plasma concentration and AUS (area under the concentration-time curve) for each drug.

EXAMPLE 2
The treatment protocol combination only with compound 1
According to this protocol, in order to show the antiviral activity of one administration regimen for patients with an HIV-seronegative reaction of compound I obtained with compound 1, compound I is administered at a dose of 600 mg three times a day, and compound 1 is administered 600 mg three times a day. Antiviral activity is measured before and during treatment by a combination by measuring serum levels of HIV p24 antigen, serum levels of HIV RNA, and CD4 lymphocyte count.

EXAMPLE 3
A combination pharmacokinetic evaluation protocol for treatment alone with compound 11
This is a cross-sectional protocol of a multi-dose three-phase treatment of randomly selected HIV-infected patients to evaluate the pharmacokinetics and safety of co-administration of compound I and compound 11.

 Twelve randomly selected HIV-infected patients receive three different treatments, consisting of dosing for a full seven days and one additional dose of active compound I and compound 11 placebo (treatment A); placebo compounds I and compounds 11 (treatment B); and active compounds I and active compounds 11 (treatment C). These types of treatment are described in Table 2 (see end of description).

 Compound I is taken in three 200 mg capsules, and compound 11 is taken in three 200 mg capsules. Placebo capsules correspond to both active compound I and active compound 11.

 Compound I or an appropriate placebo is taken every 8 hours. Potential subjects are assessed by the acceptability of a complete medical history, objective examination (including vital signs with orthostatic indicators) of an 12-lead ECG, and laboratory testing (including determining the amount of CD4) for approximately one month from the start of the study.

 For safety analysis, blood and urine are taken during each treatment period for laboratory safety tests, and a physical examination is performed before the first dose is taken (day 1) and on the day of the last dose (day 8) of each treatment period. Additionally, an ECG with 12 leads is taken before and after 1 hour after the first dose, as well as 1 hour after the last dose of each treatment period. Indicators of vital functions, including orthostatic indicators, are usually measured on a schedule on the first and last days of doses. Patients are given one day during the week of taking the medicine (the same day of taking the medicine for each treatment for an individual patient - 3, 4 or 5 days) for taking the medicine under supervision, monitoring side effects and monitoring vital signs. Patients have daily observation cards to record the time of taking all doses of the drug and notes on any adverse manifestations during each treatment period. A safety assessment after the end of the regimen, consisting of laboratory tests for safety, an objective examination and an ECG, is performed 24 hours after the last treatment.

 During treatment A, B and C, blood samples are taken to determine the plasma content of L-735524 and compound 11 through 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the last dose (day 8). The pharmacokinetic parameters that are tested include the maximum plasma concentration and AUC (area under the concentration-time curve) for each drug.

EXAMPLE 4
The treatment protocol combination only with compound 11
According to this protocol, in order to show the antiviral activity of one admission regimen for patients with an HIV-seronegative reaction of compound I obtained with compound 11, compound I is administered at a dose of 600 mg three times a day, and compound 11 is administered 600 mg three times a day. Antiviral activity is measured before and during treatment by a combination by measuring serum levels of HIV p24 antigen, serum levels of HIV RNA, and CD4 lymphocyte count.

EXAMPLE 5
Protocol pharmacokinetic evaluation of treatment with a combination only with compound III
This is a cross-sectional protocol for multidose three-phase treatment of randomly selected HIV-infected patients to evaluate the pharmacokinetics and safety of co-administration of compound I and compound III.

 Twelve randomly selected HIV-infected patients receive three different treatments, consisting of dosing for a full seven days and one additional dose of active compound I and compound III placebo (treatment A); placebo compounds I and compounds III (treatment B) and active compounds I and active compounds III (treatment C). These treatments are described in Table 3 (see end of description).

 Compound I is taken in three 200 mg capsules, and compound III in three 200 mg capsules. Placebo capsules correspond to both active compound I and active compound III.

 Compound I or an appropriate placebo is taken every 8 hours. Potential subjects are assessed by the acceptability of a complete medical history, objective examination (including indicators of vital functions with orthostatic indicators), an 12-lead ECG and laboratory testing (including determination of the number of CD4) for approximately one month from the start of the study. For safety analysis, blood and urine are taken during each treatment period for laboratory safety tests and a physical examination is performed before the first dose is taken (day 1) and on the day of the last dose (day 8) of each treatment period. Additionally, an ECG with 12 leads is taken before and after 1 hour after the first dose, as well as 1 hour after the last dose of each treatment period. Indicators of vital functions, including orthostatic indicators, are usually measured on a schedule on the first and last days of doses. Patients are given one day during the week of taking the medicine (the same day of taking the medicine for each treatment for an individual patient - 3, 4 or 5 days) for taking the medicine under supervision, monitoring side effects and monitoring vital signs. Patients have daily observation cards to record the time of taking all doses of the drug and notes on any adverse manifestations during each treatment period. A safety assessment after the end of the regimen, consisting of laboratory tests for safety, an objective examination and an ECG, is performed 24 hours after the last treatment.

 During treatment A, B and C, blood samples are taken to determine the plasma content of compound I and compound III after 0, 025, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after taking the last dose (day 8). The pharmacokinetic parameters that are tested include the maximum plasma concentration and AUC (area under the concentration-time curve) for each drug.

EXAMPLE 6
The treatment protocol is combined only with compound III.

 According to this protocol, in order to show the antiviral activity of one administration regimen for patients with an HIV-seronegative reaction of compound I obtained with compound III, compound I is administered at a dose of 600 mg three times a day, and compound III is administered 600 mg three times a day. Antiviral activity is measured before and during treatment by a combination by measuring serum levels of HIV p24 antigen, serum levels of HIV RNA, and CD4 lymphocyte count.

EXAMPLE 7
Protocol pharmacokinetic evaluation of treatment with combination only with compound IV
This is a cross-sectional protocol for multidose three-phase treatment of randomly selected HIV-infected patients to evaluate the pharmacokinetics and safety of co-administration of compound and compound IV.

 Twelve randomly selected HIV-infected patients receive three different treatments, consisting of dosing for a full seven days and one additional dose of active compound I and compound IV placebo (treatment A); placebo compounds I and compounds IV (treatment B) and active compounds I and active compounds IV (treatment C). These treatments are described in Table 4 (see end of description).

 Compound I is taken as three 200 mg capsules and compound IV is taken as three 200 mg capsules. Placebo capsules correspond to both active compound I and active compound IV.

 Compound I or an appropriate placebo is taken every 8 hours. Potential subjects are assessed by the acceptability of a complete medical history, objective examination (including indicators of vital functions with orthostatic indicators), an 12-lead ECG and laboratory testing (including determination of the amount of CD4) for approximately one month from the start of the study. For safety analysis, blood and urine are taken during each treatment period for laboratory safety tests and a physical examination is performed before the first dose is taken (day 1) and on the day of the last dose (day 8) of each treatment period. Additionally, an ECG with 12 leads is taken before and after 1 hour after the first dose, as well as 1 hour after the last dose of each treatment period. Indicators of vital functions, including orthostatic indicators, are usually measured on a schedule on the first and last days of doses. Patients are given one day during the week of taking the medicine (the same day of taking the medicine for each treatment for an individual patient - 3, 4 or 5 days) for taking the medicine under supervision, monitoring side effects and monitoring vital signs. Patients have daily observation cards to record the time of taking all doses of the drug and notes on any adverse manifestations during each treatment period. A safety assessment after the end of the regimen, consisting of laboratory tests for safety, an objective examination and an ECG, is performed 24 hours after the last treatment.

 During treatment B, B and C, blood samples are taken to determine the plasma content of compound I and compound IV at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the last dose (day 8). The pharmacokinetic parameters that are tested include the maximum plasma concentration and AUS (area under the concentration-time curve) for each drug.

EXAMPLE 8
Treatment Protocol Combination Only with Compound IV
According to this protocol, in order to show the antiviral activity of one admission regimen for patients with an HIV-seronegative reaction of compound I obtained with compound IV, compound I is administered at a dose of 600 mg three times a day, and compound IV is administered 600 mg three times a day. Antiviral activity is measured before and during treatment by a combination by measuring serum levels of HIV p24 antigen, serum levels of HIV RNA, and CD4 lymphocyte count.

 Although the above description illustrates the principles of the present invention by way of examples given for the purpose of illustration, it should be understood that the practice of the invention encompasses all ordinary variations, adaptations, or modifications as falling within the scope of the following claims and their equivalents.

Claims (7)

1. A method of inhibiting HIV protease, preventing or treating HIV infection or treating AIDS, comprising administering to a patient in need thereof N- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl- 4 (S) -hydroxy-5- (1- (4- (3-pyridylmethyl) -2 (S) -N '- (tert-butylcarbamoyl) piperazinyl)) pentanamide (component A) or a pharmaceutically acceptable salt thereof in combination from

(component B) or a pharmaceutically acceptable salt thereof.  2. The method of claim 1, wherein component A and component B are administered in capsule form.  3. The method according to p. 1 or 2, in which component A or its pharmaceutically acceptable salt is administered orally, with a dosage of 40-4000 mg per day.  4. The method according to PP. 1, 2 or 3, in which component A or a pharmaceutically acceptable salt thereof is administered in an amount of 200-1000 mg.  5. The method according to PP. 1-3 or 4, in which component B is administered orally, with a dosage of 100-4000 mg per day.  6. The method of claim 5, wherein the dosage of component B is 100 mg. 7. A pharmaceutical composition suitable for inhibiting HIV protease for preventing or treating HIV infection, AIDS or ARC (AIDS-associated complex), containing an effective amount of N- (2 (R) -hydroxy-1 (S) -indanyl) - 2 (R) -phenylmethyl-4 (S) -hydroxy-5- (1- (4- (3-pyridylmethyl) -2 (S) -N '- (tert-butylcarbamoyl) piperazinyl)) pentanamide (component A) or its pharmaceutically acceptable salt and compounds of the formula

(component B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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