GB2224649A - Fusidic acid anti-viral compositions - Google Patents

Abstract

A pharmaceutical composition, in particular for use in the treatment of viral infections, comprises fusidic acid, or a pharmaceutically acceptable derivative or salt thereof, preferably sodium fusidate, together with ascorbic acid. These components have been found to exhibit considerable synergistic activity against the HIV virus in particular.

Description

ANTIVIRAL COMPOSITIONS This invention relates to a synergistic pharmaceutical composition containing fusidic acid, a compound related thereto or a salt thereof.

Fusidic acid (BP) SQ 16603, ent - 16 dt - acetoxy - 3 ss , llss -dihydroxy 4ss, 8ss ,146- trimethyl - 18 - nor 10α cholesta (17Z ) - 17(20),24 - dien - 21 oic acid hemihydrate (C31H48O6. H20) is an antimicrobial substance which can be produced by the growth of certain strains of Fusidium Coccineurr (K. Tubaki).

It has the structural formula:

Fusidic acid is described, together wit salts and solvates thereof, in GB-A-930786. It is active against Gram.-positive bacteria and also against Gram-negative cocci. The most commonly used form is sodium fusidate, which has been found particularly useful against staphylococcal infectic,,s.

It is sold under the trade mark FUCIDIN.

Compounds related to fusidic acid, notably the 3- and/or 11- dehydro derivatives and 24,25- dihydro derivatives and their salts, are disclosed in GB-A-992276.

These derivatives have also been found to have useful antibacterial properties.

Fusidic acid and its derivatives have ot hitherto been thought to have any significant antiviral activity.

It has however now been found that when administered ogether with ascorbic acid (vitamin C) the two compounds together exhibit a synergistic action against certain viruses.

The present invention accordingly consists in G pharmaceutical composition, in particular for the treatment of viral infections, comprising fusidic acid, a pharmaceutically acceptable derivative or salt thereof and ascorbic acid.

The invention also consists i the use of te above two components in the preparation cf a medicament for the treatment of viral infectlons, notably infectltns with -h Herpes Simplex, Venereal Herpes and other viruses.

Ascorbic acid (L-ascorbic acid or vitarin C 15 an essential dietary factor which prevents sourvy and also increases resistance to infection. It is assured to act as an oxidation-reduction catalyst in the cell. It has uses in nutrition, as a flavouring agent and preservative in foodstuffs, as an oxidant in bread doughs and as a reducicing agent in analytical chemistry. It is not thought to exhibit any anti viral activity on its own.

The composition of the invention has been found to exhibit considerable synergls ic activity against the HI virus. This virus is responsible for the acquire immune defficiency syndrome (AIDS) where while blood cells bone rrarrow cells are attacked, thus deswrcyi, the natural immune system of the body. Ultimately it tend also to attack the central nervous system.

Ascorbic acid is administered together with fusidic acid or a derivative or salt thereof in high doses to produce the required synergistic effect. The two compounds produce high concentrations in the body fluids, including the leucocytes or white blood cells (WBC), bone marrow cells (B cells) and central nervous system (CNS cells) where their synergistic action produces a viricidal effect on the virus present in the cells. The effect is to inhibit the entry of the virus into bone marrow cells and to destroy viruses that have already entered.

The recommended initial term of treatment is 30 to 60 days at the end of which most of the viruses are likely to have been destroyed. The treatment can be continued thereafter if necessary.

As regards side effects, mild diarrhoea has been observed in some patients. Liver functicn tests should be carried out in cases of pre-existing lIver dys@unction because of the action of fusidic acid.

The preferred dosage ranges are as follows:- (1) Sod. Fusidate 500 mg ) Dos Ascorbic acid 1500 mg)Dose x 3 per day x 30-60 days.

or x 4 per day x 3C-6C days.

(2) Sod. fusidate 500 mg ) Do Ascorbic acid 1000 mg)Dose x 3 per day. For 30-60 days or x 4 per day. For 30-60 days (3) Sod. fusidate 250 mg ) Ascorbic acid 1000 mg) Dose x 3 per day. For 30-60 days or x 4 per day. For 30-60 days CHILDREN UNDER 10 years (4) Sod. fusidate 125 mg ) Dot Ascorbic acid 500 mg ) x 3 per day. For 30-60 days or x 4 per day. Fcr 30-tO days.

Of the above, dosage (1) is preferred for adults of normal bodyweight, while (2) or (3) would be appropriate for patients of lower bodyweight and more particularly those more susceptible to side effects. In each case, the 4 per day dosage rate is intended for patients with AIDS- symptoms while the 3 per day dosage rate is for patients who are HIV positive but do not yet have such symptoms.

A patient suffering from liver dysfunction, which might be aggravated by the fusidic acid, should generally be on dosage rate (3).

The 500 mg dose of sodium fusidate is therapeutically equivalent to approximately 714 grams of fusidic acid.

The sodium salt, when administered orally, will be hydrolysed to the free acid in the stomach and digestive tract. Alternatively, buffered solutions cf fusidic acid and ascorbic acid may be administered intraveneously cr by means of suppositories. For oral administration, the medicament may be formulated In dosage units In cats or in tablets or pills which may be enteric coated.

The synergistic effect of the two components has been found to be viricidal in bone marrow tissue, white bloom cells, marrow cells and the central nervous system whether administered orally or intravenously. The first Indicator that bone marrow cells are free from the virus attack is the rise in the WBC count which generally occurs within six weeks from the start of the treatment. The components of the composition also cross the blood/brain barrier to free the central nervous system from the virus.

CLINICAL TRIALS Patient (1): A Ugandan female aged 20 years found to be HIV positive. The patient complained of an bitchy popular rash, body weakness, loss of appetite, abdominal pains ano fever. She had chronic anaemia, the haemoglobln t sr ) count being l0.19g/lOOml, with a WBC count of 2000 mm -3.

She was also suffering from Neutropaenia and Lymphopaenia with an erythocyte sedementation rate (ESR) of 57 mr/h (Westergreen). She also had oral and vaginal monilia.

The fever was attributed to the activity of the HIV virus.

The patient also showed symptoms of central nervous system involvement in that she became uncooperative, refusing medication and nursing care. A subsequent blood test showed that the Hb level had fallen to 8.3 g/lOOml, but tests for syphilis and hepatitis proved negative. She was treated with Ketocomopole 200 mg daily to combat the fungal infections. Approximately one month later, by which time the Hb count had fallen to 7.2 g/100 ml and the WBC count to 1100 mum 3, she was started on a course of sodium fusidate and ascorbic acid. These medicaments were administered orally, in powder form, at the above dosage rate (1) four times a day. Treatment was continued for 60 days.

After 21 days the swinging fever which she had been suffering and the skin rash disappeared. The patient gained strength and her mental status improved gradually to normal.

After three months, the WBC count had risen tc 3, 500mum with lymphocytes (L)50% and Neutrophlvles (N)50%, and the Hb level to 10.2 g/100 ml. The ESR had fallen to 40 m,m/h and the platelet count was normal. The patient's appetite improved and the mcnilia Infections disappearec. After three and a half months from the start of treatment the WBC count had risen to 4,200 mm After 5 months the improvement was still maintained.

Patient (2): An adult male, found to be HIV positive, had a recurrent fever and skin rash. Blood tests showed -3 the following: Hb 13.8 g/100 ml, WBC 5280 mm 3, N = 40%, L = 58 /c, M (monocytes) = 0.4%, ESR = 20 mm/h. Malarial parasites were also found in the blood and treatment for this was started.

The patient was treated with sodium fusidate and ascorbic acid with the same dosage rate and conditions as Patient (1). After seven days, the Hb count had risen to 17.4 g/100 ml, and the ESR was 19 mm/h and the WBC count 3 had risen to 5,800 mm (N 68%, L 32%) no malarial parasites were seen. After a further eight days, the ESR had fallen to 3mm/h and the WEC had risen to 7000 mm (M = 48%, 3360/mm . L = 52% 3640/m 3).

After two months from the start of treatment the WBC was still 7000 mm and the ESR had fallen to 2 mm/h. The fever subsided and the rash disappeared.

Group of Seven patients: These patients, aged from 30 to 50 years, had all been shown to be HIV positive and EUSA sero positive. All seven satisfied the WHO clinical criteria for AIDS.

The patients were given a treatment similar to that of patients (1) and (2), for two weeks. Subsequently all reported subjective improvement with a reduced temnerature.

improved appetite and, in some cases, a gamin In weigh.

Individual results are as follows: Patient (3), adult female.

After eight weeks: a) Weight fell slightly, from 4 kg. to 48 kg.

b) ESR remained static at 115 mm/h (Westergreen).

c) WBC rose from 4150 to 4250 mm d) Hb remained substantially unchanged at 9-10 g/100 ml.

e) Opportunistic Infections remained.

Impression: Marginal improvement indicated by rise in white blood cell count and arresting of the increase in ESR.

Patient (4), male.

After eight weeks: a) Weight increased from 53 kg. to 55 kg.

b) ESR fell slightly from 100 to 97 mm/h (Westergreen).

c) WBC fell from 4760 to 4320 mm d) Skin rash persisted.

Impression: little sign of overall improvement, but slight improvement in ESR indicates a slowing down of the disease.

Patient (5), male.

After eight weeks: a) Weight fell from 50 to 38 kg.

b) ESR rose from 100 to 155 mm/h (worse).

c) WBC rose from 4650 to 4800 mm (better).

Patient (6) male, suffering from malabsorption syndrome, anaemia, diabetes and hypertension.

After 8 weeks: a) Weight increased from 58 to 59 kg.

b) ESR fell from 86 to 55 mm/h.

c) WBC fell from 11,000 to a more normal 6000 mm 3, the abnormally high initial level indicating a disproportionately high neutrophile content and being attributable te the AIDS-related complex itself.

d) Anaemia improved.

e) HypertensIon disappeared.

f) Liabetes disappeared.

Impression: substantial improvement. Patient was able to return to work.

Patient (7) male, suffering from fever and mycotic infection.

After 8 weeks: a) Weight increased from 45 to 48 kg.

b) ESR remained unchanged at 120 mm/h.

c) WBC increased from 6000 to 6150 mm d) complete remission of fever.

e) Complete remission of mycotic infection.

Impression: Significant improvement.

These cases are still under treatment at the tie of filing this applIcation.

Salts of fusidic acid other than the sodium salt can also be used in the composition of the invention. Apart from sodium, the diethanolamine salt is also suitable, as are the potassium, ammonium, triethylamine, piperidine, morpholine, cyclohexylamine and monoethanolamine, all of which, unlike fusidic acid itself, are water soluble.

Less water soluble salts which could also be considered are the calcium, magnesium, dibenzyl-ethylene-diamine, benzylbeta-phenyl-ethylamine and procaine salts.

Compounds closely related to fusidic acid which may also be used in accordance with the invention induce 3-dehydrofusic acid, ll-dehydrofusidic acid, 3,11-dihydrofusidic acid, 3-dehydro-24-25-dihydrofusidic acid, 11dehydro-24-25-dihydrofusidic acid and 3,11-didehydro-24-25- dihydrofusidic acid. These compounds can be obtained as for example as disclosed in GB-A-992276.

In a preferred treatment in accordance with the invention, reccvery of the bone marrow cells may be assisted by administering folio acid (Vital E12,.

Claims (9)

1. A pharmaceutical composition comprising fusidic acid, or a pharmaceutically acceptable derivative or salt thereof, and ascorbic acid.

2. A pharmaceutical composition according to claim 1 which comprises 3-dehydrofusidic acid, ll-dehydrofusidic acid or 24,25-dihydrofusidic acid, or a salt thereof.

3. A pharmaceutical composition according to claim 1 or claim 2 wherein the fusidic acid or derivative is present in the form of its sodium salt.

4. A pharmaceutical composition according to claim 3 wherein the weight ratio of ascorbic acid to sodium fusidate is in the range from 2:1 to 4:1.

5. A pharmaceutical composition according to claim 4 in dosage units of 625 to 2000 Mg.

6. A pharmaceutical composition according to any preceding claim for use in the treatment of viral infections.

7. A pharmaceutical composition according to claim 6 for use in combating the HIV, Herpes simplex or venereal herpes viruses.

8. The use of fusidic acid, or a pharmaceutically acceptable derivative or salt thereof, together with ascorbic acid, in the preparation of a pharmaceutical composition for use in the treatment of viral infections.

9. A pharmaceutical composition according to claim 1, substantially as herein described and exemplified.