JPH0291027A - Improvement in organic compound - Google Patents

Abstract

PURPOSE: To obtain a medicinal composition useful for controlling diseases induced by retrovirus (esp, HIV-1 virus), containing as active ingredient, octoleotide in free form, in the form of medicinally permissible salt, or in complex form. CONSTITUTION: This medicinal composition for controlling diseases induced by retrovirus contains octoleotide of the formula in free form, in the form of medicinally permissible salt, or in complex form, in combination with at least one kind of support or diluent for medicinal use. This composition is especially useful as a controlling agent for diseases induced by HIV-1, virus, HIV-1 virus replication inhibitor, or AIDS treatment agent. The octoleotide is effective against diseases caused by retrovirus (esp. HIV-1) except serious diarrhea which cannot be treated by antibiotics and common antidiarrhetic therapies, and has especially favorable therapeutic effect in initial infectious phase.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to a therapeutic agent for retroviral diseases.

[Summary] The present invention relates to the use of a short somatosfutin analog known as octreotide and having the following formula in the control of retroviruses, particularly HIV-1-induced diseases. It is something.

[Summary of the Invention] This invention provides novel uses, particularly new pharmaceutical uses, of a somatostatin analog known as octreotide, that is, a compound represented by the following formula, as well as pharmaceutical compositions incorporating the above-mentioned compound, and pharmaceuticals adapted for the above-mentioned uses. It relates to the use of the above compounds for the manufacture of compositions.

BACKGROUND OF THE INVENTION Octreotide is known to inhibit the secretion of various hormones, particularly growth hormone, and to have modulating effects on physiological functions, including several effects on the gastrointestinal tract. This compound was produced, for example, at a rate of 3.0 tn/day over a period of 35.4 months (no change in content).
It shows good drug resistance up to the age of 100,000 people.

Non-toxic levels are e.g.
/ 9/day, dog intravenous administration (26 weeks long-term administration) 05
M9/kg/day.

Octreotide has been found to have beneficial effects in patients with severe secretory diarrhea, e.g. promoting absorption of water and electrolytes and prolonging small intestinal transit time [William et al., Br, Med. ,
J, ) 1984, vol. 289 + p. 027-1028, Smith et al., Journal of Pediatric Gastroenterology and = 3/-3
, PediatrGasLroenterol,
Nutr, ) 1987, Vol. 6, p. 710,716].

Persistent diarrhea can be a major problem in the clinical management of AIDS, for example in the late stages, requiring hospitalization and intravenous fluid and electrolyte infusion therapy.

More recently, severe cases of e.g. There are reports of administration of octreotide to a small number of AIDS patients suffering from Cryptosporidium-associated diarrhea [Gatz et al., Drug Intelligence.
And Clinical Fa 077-(Drug I
intelligence and C11nica
l Pharmacy) 1988 Volume 22 134
-136 pages, Collins et al., Annals of Internal Medicine
Internal Medicine) 1988, Vol. 5, pp. 708-709. A decrease in the amount and frequency of defecation was observed. According to Collins et al., this beneficial effect appears to be related to the compound's effect on intestinal transit rather than its effect on immunity.

[Structure of the Invention] Surprisingly, the specification of somatostatin short chain analogs Octreo in free form or in pharmaceutically acceptable salt form? (
(No change in content) It has been found that Tide exhibits activity against retroviruses, particularly human retroviruses, and in particular HIV-1.

Octreotide can exist, for example, in free form, salt form or complex form thereof. Acid addition salts can be formed, for example, with diabetic acids, folimer acids, and non-ethyl acids. Such acid addition salt forms include, for example, hydrochloride and acetate.

The complex is, for example, octreotide combined with an inorganic substance, such as Ca.
Formed upon addition of salts and inorganic salts such as Zn salts or hydroxides and/or polymeric organic substances.

Retroviral diseases, which have recently received particular attention,
For example, common diseases such as adult T-cell disease (ATL) and acquired immunodeficiency syndrome (AIDS).

A review of human retrovirology can be found in Nature.
re) Vol. 317, p. 395 (1985). It is generally accepted that ATL is caused by the human retrovirus HIV-1.

Preface to the Specification (No change in content) AIDS, which is currently spreading throughout the world at an unprecedented rate, is an infectious disease caused by HTLV-[1 (HIV-1).

HTLV-1 and HIV-1 are lymphocytic and bipolar in helper T t, IIl IIl. H
There is also a requirement for neurotropism for IVl.

In AIDS, there is an incubation period of several years after the initial infection, during which the virus can be detected in the infected person, but the immune system
No harm is seen.

According to the present invention, it has been found that diseases caused by retroviruses, especially HIV-1, and especially those other than severe diarrhea that do not respond to antibiotics and conventional antidiarrheal therapy, can be treated by administration of octreotide. In particular, octreotide was found to have a particularly good therapeutic effect in early infected + eyes.

This invention therefore provides a method for the control of retroviruses, particularly HIV-1-induced disease, in patients in need of treatment, particularly non-diarrheal diseases that do not respond to antibiotics and conventional anti-diarrheal therapy, and which The present invention provides a method comprising administering an active form of octreotide in the form or pharmaceutically acceptable salts or complexes of octreotide (no change in content).

The use of octreotide can be demonstrated in in vitro tests, for example testing the effect on HIV-lutrovirus replication.

The virus strain used was the HIV-1 isolate HTLV-
III. Virus production was measured using two systems.

D1, Peripheral blood mononuclear cells (PBMCs) isolated by the Capracell-MN method and experimentally infected with HTLV.

2. Human lymphoblast cell line chronically infected with HTLV-1 (1 (9 cell lines).

(Infection and culture) PBM cells were stimulated with PHA-P (Sigma) for 3 days,
They were then treated with polybrene (2 μg/5u2) for 2 hours before infection. For infection, cells (l x 10@c/Wf) were incubated with the above positive supernatant for 24 hours using a supernatant positive for the reverse transcriptase activity test. After removal by low-speed centrifugation, the cells were incubated with 10% IL-2 ( 'J' was placed in fresh medium containing % fetal bovine serum (Gibco Tsuji), antibiotics and octreotide.

1-19 cells were cultured in RPM+-1640 medium (Gibfu) using only 10% fetal bovine serum and antibiotics.

The pattern of 1-11 V-1 production was examined using the above two cell lines.

a) Ability of cells to produce virus particles by upper ln with reverse transcriptase activity. To evaluate this activity, supernatants were collected twice a week, and the supernatants were collected twice a week, and the supernatants were collected twice a week.
147, lines 326-335 (1985)
Measured as described.

b) Viral protein synthesis by immunofluorescence. In this study, immunoglobulins obtained from a pool of tV-1 seropositive sera (ELISA method and Western blot) were first precipitated with ammonium sulfate and then partially purified on a DEAE cellulose column. Reprint of OIM specification (no changes in content) Elution was done with phosphoric acid buffer.

c) Induction of /n/thium (fused cell) production.

The above H9/HTLV-III and PBMC/HT
In in vitro experiments using the LV-III system, oftreotide inhibited HIV V1 at concentrations between 10-'' and 10-molar.

In peripheral blood cell (PBMC) culture, to-” molar?
Octreotide at a degree of H
Inhibits IV-1 replication, peaking at 98% at position 158
Met. The inhibitory potency of 10-” molta scutreotide was lower. The inhibition peak was at the 158th point, 93
%, inhibition extended to 80% only in 6 days. ! 0-
For 6 moles of octreotide, 15.25 and 37
A curve showing an inhibition peak on each day was obtained.

For I-11V-1 cultures in H9 cells, the optimal inhibitory concentration of octreotide was 10-''Molar.

At this concentration, the inhibition peak was 87% on day 17 [''. Even at the 81% peak on the 33rd day, octreotide 1
Good inhibition was obtained at 0-"Mole.

Inhibition was divided into two peaks when infected H9 cells were cultured for 55 days, but there was only one peak when infected PBMCs were cultured for 37 days.

Regarding the effect of octreotide on uninfected H9 cells, it was concluded that octreotide has no toxicity against the lymphoblastoid cell lines mentioned above even at optimal inhibitory concentrations such as 10-"M and IQ-"M. It was done. 10-”
With M. octreotide, the average survival rate was 77.8% (1
0-''M was 888%), so there was slight toxicity.

In a cell count test using a Coulter counter, octreotide showed no antiproliferative effect on 89 cells cultured for 1 month.
It turned out that it didn't show up.

Therefore, octreotide is useful in the treatment of retroviruses, especially human retroviruses, especially HIV-1-induced diseases, especially AIDS disease, especially those other than diarrhea that do not respond to antibiotics and conventional diarrhea therapy. Octreotide is also useful in preventing the progression of HIV positivity (AIDS-related complex) to AIDS. In this indication, the appropriate dosage will, of course, vary depending on, for example, the method of administration, the particular condition of the patient to be treated and the desired effect.

Additionally, the dosing regimen generally includes, for example, an initial daily dose or
Administration of loading (+oadIng) J dose followed by ffi depending on serum concentration, e.g. by regular RIA monitoring.
Adjustments (usually reductions) to obtain appropriate long-term drug serum concentrations require adjustment for the individual patient undergoing treatment. However, in general, satisfactory results in animals are obtained with daily doses of about 0.01 μ9/9 to about 1000 μ9/9. In large mammals, such as humans, the indicated daily dose is at or above or below the range used for the treatment of gastrointestinal pancreatic endocrine tumors such as bipoma or acromegaly, such as from one-tenth to about ten times .

For example, a suitable daily dose for an adult patient is about 0.00
Depending on the range from 1 to about 20 mg, further suitable unit dosage forms for parenteral administration are from about 0.0005 to about 1
Contains up to 0 mg of octreotide. For example, a suitable daily subcutaneous dose is about 0.001 to about 1 mg, preferably 0.01 O to 1 mg.

Octreotide may be administered by any suitable route, in particular nasally, enterally, in particular orally, eg tablets, capsules or parenterally, eg as an injectable solution or suspension.

This invention relates to the use of retroviruses, especially HIV-1, in free form or in the form of pharmaceutically acceptable salts or complexes, together with at least one pharmaceutical carrier or diluent. Pharmaceutical compositions containing octreotide for controlling diseases caused by other conditions are also proposed. The above compositions may be manufactured in conventional manner.

In another alternative embodiment, the invention provides pharmaceutical compositions for the control of diseases caused by retroviruses, especially HIV-1! Also provided is the use of octreotide for the production of octreotide.

[Example] An example of the production of a pharmaceutical suitable for administration of octreotide is shown below.

In an ampoule for subcutaneous injection, Formulation Example 1 Octreotide* 0.05 mg Mannitol 45.0 mg Lactic Acid (88%)
Add 3.4 mg NaHCO, p
Add water (for injection) to H4,2 and add carbon dioxide to 1ml Appropriate amount Preparation example 2 Octreotide* 0.2mg NaC
17.5mg lactic acid (88%) 3.4mgNa1
Water (for injection) was added to pH 4.2, and carbon dioxide was added to 1 ml at a concentration of 87% peptide acetate (gm).

By standard techniques, 1IA1 is 5% under carbon dioxide aeration.
0 liters were added to produce the desired amount of octreotide, initially dissolved in water. The composition was passed for 6 minutes and then introduced into ampoules under aseptic conditions.

If desired, lactic acid can be replaced with acetate buffer. The above compositions were administered once a day to patients suffering from diseases caused by retroviruses, particularly AIDS (HIV-1), and more particularly by other than the diarrheal symptoms described above.

Patent applicant Sand Akchengesellschaft representative
1-person procedural amendment (voluntary) D 444 revision 1/a - 1st reference 3゜Relationship with the case

Claims (4)

[Claims] (1) A pharmaceutical composition for controlling retrovirus-induced diseases, which contains octreotide in free form or in a pharmaceutically acceptable salt or complex form, together with at least one pharmaceutical carrier or diluent. (2) The pharmaceutical composition according to claim 1, which is used for controlling HIV-1 virus-induced diseases. (3) The pharmaceutical composition according to claim 1, which inhibits replication of the HIV-1 virus. (4) The pharmaceutical composition according to claim 1, which is for treating AIDS.