WO2012130646A1

WO2012130646A1 - N-acetyl-l-cysteine for the treatment of dysmenorrhea

Info

Publication number: WO2012130646A1
Application number: PCT/EP2012/054745
Authority: WO
Inventors: Tiziana Parasassi; Maria Grazia PORPORA
Original assignee: Iasomai Ab
Priority date: 2011-03-25
Filing date: 2012-03-19
Publication date: 2012-10-04

Abstract

The invention relates to a composition of NAC for the treatment of dysmenorrhea, such as primary dysmenorrhea, in a human or mammalian animal patient. It also relates to such a composition for the use in combination with other treatment modalities used in the treatment of dysmenorrhea. In addition an effective dose regimen of NAC in the treatment of dysmenorrhea is proposed. Side effects of this treatment are virtually absent and, in particular, this treatment does not involve hormones and does not hinder pregnancy.

Description

N-ACETYL-L-CYSTEINE FOR THE TREATMENT OF DYSMENORRHEA

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising N-acetyl-L- cysteine useful for the treatment of dysmenorrhea.

BACKGROUND

Dysmenorrhea is a medical condition associated with pain before and/or during

menstruation. The pain may range from normal menstrual pain to pain that is so severe that it affects the daily life of women affected. It is a very common problem of women in reproductive age, affecting about 10-20% of females in their late teens and early twenties. The pain is often so severe that the women have to stay in bed causing absence from work and school.

Dysmenorrhea is classified into primary and secondary dysmenorrhea. Women with primary dysmenorrhea have a normal pelvic anatomy, whereas in women with secondary dysmenorrhea the pain is associated with an underlying disease, disorder or structural abnormality of the pelvic organs. The cause of primary dysmenorrhea is not known, but it is associated with the release of prostaglandins that regulate myometrial contractility, leading to uterine contractions, ischemia and pain. Vasopressin may also be involved, increasing uterine contractility and causing ischemic pain due to vasoconstriction.

The primary choice for treatment of dysmenorrhea is the use of nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, naproxen, mefenamic acid and aspirin. The efficiency of these drugs vary with patient and severity of symptoms and they may cause side effects such as nausea, dyspepsia, peptic ulcer, and diarrhea, especially when used regularly or over longer periods of time. It has been suggested that the degree of potency of analgesics in alleviating dysmenorrhea is partly related to their effectiveness in depressing prostaglandin synthesis or its action.

Also, Ca2+ antagonist agents/calcium channel blockers such as nifedipine and verapamil have been shown to reduce dysmenorrhea suggesting that not only prostaglandins may play a role in the hypercontractibility of the uterus i.e. a multitude of mechanisms may account for the pain. This is further supported by studies showing that also hormonal preparations that inhibit ovulation may have a pain alleviating effect. For example, oral contraceptive pills may be used. Hormonal treatment with vasopressin receptor antagonists has also been suggested. Hormonal methods of treatment may however also have undesirable side effects, such as amenorrhea, and not all women wish to use hormonal treatment or contraceptives.

Furthermore, non-pharmacological methods for the relief of pain like TNS/TENS

(transcutaneous electrical nerve stimulation), special diets, exercise and acupuncture have been demonstrated to reduce the pain in dysmenorrhea.

Other pharmacological treatments that have been proposed include treatment with glycerine trinitrate, terbutaline (P2-adrenergic receptor agonist), danazol (modified testosterone) and leuprolide (gonadotropin-releasing hormone agonist).

N-acetyl-L-cysteine (hereinafter referred to as NAC) is a well-known drug, which has been used mainly as a mucolytic agent and in the treatment of paracetamol poisoning. In recent years it has also been acknowledged as having other beneficial properties, such as being anti-inflammatory and anti-proliferative, and has been suggested for the treatment of a variety of different disorders and symptoms such as schizophrenia, diabetes and cancer.

The present inventors have found that NAC provides pain relief in patients with dysmenorrhea. Treatment with NAC is virtually without any side effects and the effects of hormonal treatment are avoided.

PRIOR ART

In studies by Yan Wo and Sun- Wei Guo (Gynecologic and Obstetric Investigation (2006), Vol. 62, No. 4, pages 193-205; European Journal of Obstetrics & Gynecology and

Reproductive Biology, (2008), Vol. 137, pages 198-203); patent document US

2007/0287676 Al) the effect of NAC on human endometrial stromal cells was investigated and compared to other agents proposed for the treatment of endometriosis. Dysmenorrhea is disclosed as a symptom of endometriosis.

Linda French (American Family Physician (2005), Vol. 71, No. 2, pages 285-291) discloses a review of current methods of treatment of dysmenorrhea.

The use of NAC for treatment of dysmenorrhea is described in US 6,476,072. In CH

694 034 injection solutions containing NAC together with other active ingredients for the treatment of pain are described. Further WO 2011/036265, published after the priority date of the present application describes NAC for the treatment of endometrioses.

Other background art, describing the molecular effects of NAC in the treatment of cancer, include T. Parasassi, et. al. (Cell Death and Differentiation (2005), Vol. 12, No. 10, pages 1285-1296); E. K. Krasnowska et. al. (Free Radicals Biology and Medicine 2008,

45(11): 1566-72) and A. C. Gustafsson et. al. (BMC Cancer (2005), 5:75).

OBJECTS OF THE INVENTION

It is a general object of the present invention to provide a solution to the problem of providing a pharmaceutical composition that is effective in the treatment of dysmenorrhea in mammals, including humans. In one aspect the object is to provide a pharmaceutical composition comprising N-acetyl-L-cysteine (NAC) for the treatment of dysmenorrhea in mammals, including humans. In further aspects the object is to provide a pharmaceutical composition comprising N-acetyl-L-cysteine (NAC) for use with an effective dosage regimen for the treatment of dysmenorrhea in mammals, including humans, as well as for use in combination with other pain relieving treatments.

SUMMARY OF THE INVENTION

The inventors of the present disclosure show that NAC reduces pain symptoms in patients with dysmenorrhea. These findings have led the inventors of the present invention to propose a new prescription of NAC in the treatment of dysmenorrhea, in a human or mammalian animal patient. NAC is also proposed for use in combination with other modes of pain relieving treatments, in order to enhance their pain relieving effect. In addition an effective dose range of NAC in the treatment of dysmenorrhea is proposed. Side effects of this treatment are virtually absent and, in particular, this treatment does not involve hormonal treatment and does not hinder pregnancy.

The present invention provides a pharmaceutical composition comprising N-acetyl-L- cysteine for use in the treatment of a mammal, including a human, having dysmenorrhea. In one embodiment the dysmenorrhea is primary dysmenorrhea. In another embodiment the mammal does not have endometriosis.

In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the above mentioned use, where the composition is for oral administration at a dose of N-acetyl-L-cysteine that is between 20 and 90 mg/kg/day. In another embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the above mentioned use, where the composition is for oral administration at a dose of N-acetyl-L-cysteine that is between 30 and 60 mg/kg/day. In still another embodiment the pharmaceutical composition is for administration at a dose of N-acetyl-L-cysteine that is between 30 and 45 mg/kg/day.

In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for use in combination with a second treatment that is also treatment of a mammal having dysmenorrhea. The second treatment is for example treatment with a non- steroidal anti-inflammatory drug (NSAID) such as naproxen, treatment with a Ca²⁺ antagonist agent/calcium channel blocker such as verapamil and/or a non-pharmaceutical method such as TNS/TENS.

In one embodiment the invention provides a pharmaceutical composition comprising N- acetyl-L-cysteine for the use described above where the pharmaceutical composition is protected from light. In another embodiment the pharmaceutical composition is a water soluble tablet. In still another embodiment the pharmaceutical composition contains sodium hydrogen carbonate. In one embodiment the pharmaceutical composition is a slow- release formulation and/or a formulation for gastric protection.

The treatment and/or the second treatment is for example for reducing pain in a mammal having dysmenorrhea.

In one aspect the invention provides a method for the treatment of a mammal having dysmenorrhea, comprising administering a pharmaceutical composition comprising N- acetyl-L-cysteine according to any of the above uses, dosages or compositions, possibly in combination with a second treatment that is also treatment of a mammal having

dysmenorrhea. The second treatment is for examples treatment with a non-steroidal antiinflammatory drug (NSAID) such as naproxen, treatment with a Ca²⁺ antagonist agent/calcium channel blocker such as verapamil and/or a non-pharmaceutical method such as TNS/TENS.

BRIEF DESCRIPTION OF THE FIGURES

The invention will be explained in more detail in the following description, referring to the enclosed tables, where: Table 1 shows data of patients enrolled in the study of Example 1. VAS = visual analogue scale, in this table indicating the perception of intensity of pain for each patient before onset of the study (normal or ground level).

Table 2 shows data (VAS) indicating the perception of intensity of pain for each patient before and after different modalities of treatment.

DETAILED DESCRIPTION OF THE INVENTION NAC in general

N-acetyl-L-cysteine (NAC) is a well known low molecular weight pharmaceutical drug, with the chemical formula

NAC

NAC has been found to exert molecular and physiological effects through various mechanisms. The features of NAC are mainly related to its thiol group, which makes it effective in most biochemical pathways were the gluthation (GSH) acts. NAC is processed by cells to L-cysteine and is used in the de novo synthesis of GSH, thus being considered a precursor of GSH.

NAC appears to act in all biochemical pathways where GSH does. Although details of NAC mechanisms of action are not completely understood, undoubtedly they have to be attributed to its thiol group. It thus affects the complex redox cycling of thiol groups in the cell, where several enzymes act whose redox transitions occur via the oxidation/reduction of glutathione (GSH), thereby contributing to the regulation of the oxidative state of the cell. NAC is also considered a potent antioxidant.

Of extreme physiological importance is the disulfide formation and breakage cycle, a common mechanism by which protein activity and cellular signalling is regulated. For instance, NAC is able to modulate signal transduction in cells through the redox status of sensitive cysteines of certain proteins. Enzymes such as protein tyrosine phosphatases and tyrosine kinases, for example, play pivotal roles in the control of the cell cycle, cell proliferation and differentiation, and many of them are regulated by the redox state of their cysteines.

NAC has been and still is largely used as a mucolytic agent, where the mode of action is generally attributed to the redox breakage of sensitive cysteine disulfur bridges in the mucus proteins. In addition NAC has been the prime treatment of paracetamol poisoning.

In recent years NAC has also been acknowledged as having other beneficial properties. NAC has for instance been found to inhibit proliferation and promote quiescence, further evolving in terminal differentiation. It was found that the antiproliferative effect of NAC was not related to cell death or to toxicity but, instead, was due to the activation of a physiological differentiation pathway, which can be regarded as a normalization of cell functions towards the tissue of origin. NAC has in this context been found to possess a marked antiproliferative effect on cancer cells and has also been found to be effective in the treatment of endometriosis.

NAC has further been reported to have an anti-inflammatory effect, a reason for its addition to the family of non-steroidal anti-inflammatory drugs (NSAIDs).

Contrary to the tripeptide GSH, which can be degraded already in the stomach, the simple NAC molecule freely diffuses in almost all tissues and cells. NAC pharmacokinetic studies determined a peak concentration in plasma reached in about one hour, with a half-life of about three hours. Total clearance occurs after between six and twelve hours.

An advantage in the use of NAC is the virtual absence of side effects.

NAC and dysmenorrhea

The present inventors show, in the example described below, that NAC is efficient in relieving symptoms of pain in patients suffering from dysmenorrhea.

The present inventors also show that NAC may also be used in combination with other pain relieving treatments in order to enhance their pain relieving effect. For example, NAC enhances the effect of other pharmaceutically active compounds, such as non-steroidal anti-inflammatory drugs (NSAIDs), exemplified by naproxen, of Ca²⁺ antagonist agents/calcium channel blockers, as exemplified by Verapamil, and of non-pharmaceutical treatments such as TNS/TENS.

The mechanism behind the pain relief was initially believed to be through inhibition of prostaglandin synthesis/activity. The effect that NAC has on enhancing the effect of the other treatment modalities do however indicate that other mechanisms of action may also or alternatively be involved. Given the various modes of action that NAC has in the body the pain relieving effect may be related to any or a combination of those.

Dosage regimen

For the purpose of the present invention a dosage regimen of NAC for the treatment of dysmenorrhea in a mammal, including human, was developed based on the criteria of a dosage of NAC per day which is in agreement with other current clinical treatments and is considered without undesirable side effects.

The composition of the present invention, comprising NAC for the treatment of dysmenorrhea is according to one embodiment to be administered at a dose between approximately 20 and 90 mg/kg/day. The lower limit is based on twice the dose used for mucolytic action, i.e. it is per se known to have a physiological effect. The upper limit is based on the consideration that higher doses have been found to cause gastric problems in many patients. In another embodiment of the present invention the composition comprises NAC to be administered at a dose of approximately 30-60 mg/kg/day. The lower limit has been shown to be effective in dysmenorrhea and the higher limit is known to have virtually no side effects. In still another embodiment of the present invention the composition comprises NAC to be administered at a dose of approximately 30-45 mg/kg/day. This low dosage has surprisingly been shown to be effective in dysmenorrhea. The dose may be given once a day or may be divided in two or more, preferably three or four, daily administrations of either one or two doses (e.g. pills) each, where each dose may comprise e.g. 0.15-2.7 g of NAC or preferably 0.6-1.2 g of NAC.

In one embodiment the composition is to be administered in connection to a menstrual period. Preferably treatment is started on, or one to a few days before, the first day of menstruation or when first experiencing menstrual pain. Treatment may be continued for as long as needed, e.g. until the end of the menstrual period or until the experienced pain is sufficiently low or absent. Typically, periods for treatment last for 1-7 or 2-5 days. In certain aspects of the invention NAC may also be used as a long term treatment for patients with dysmenorrhea. For instance, NAC may be administered for a period of time which is one month or more, two months or more, or preferably three months or more. To counteract a decrease in NAC plasma level after prolonged treatment NAC may be administered at the prescribed dosage in an intermittent fashion, i.e. intermittent dosage regimen/treatment. By intermittent administration or treatment is meant that the treatment is interrupted in periods, i.e. that the pharmaceutical composition is administered for a period of time, e.g. a few days, followed by an interruption in administration, where no pharmaceutical composition is administered for a period of time, e.g. for a few days. Intermittent treatment can be regular, e.g. treatment for a fixed number of days or weeks, followed by interruption for a fixed number of days or weeks. Examples include repeated schemes with treatment for 4 days followed by interruption for 3 days each week or treatment for 2 weeks followed by interruption for 1 week. A special case of regular intermittent treatment is pulsed treatment, i.e. with regular treatment and interruption duration, e.g. administration every other day or administration for two days followed by two days of interruption etc. Irregular intermittent treatment schemes that are not regularly repeated or have a more complex scheme that is repeated is also conceivable, e.g.

dependent on response to treatment. In different exemplifying embodiments of the present invention the prescribed dose of NAC is administered for 3-5 consecutive days followed by 2-4 days of interruption, or administered for 1-3 consecutive days followed by 1-2 days of interruption.

Pharmaceutical formulations

A pharmaceutical composition according to the present invention may be prepared in a manner per se known by a person skilled in the pharmaceutical art. The composition may comprise an effective amount of NAC, in accordance with the invention, as well as a suitable carrier or excipient that serves as a vehicle or medium for the active ingredient. Such carriers or excipients are known in the art and include solid materials such as citric acid, sodium citrate, sodium (acid) carbonate plus flavouring. The pharmaceutical composition is preferably adapted for oral administration. Such compositions could be administered in different forms, at present preferably as tablets. Other forms, such as capsules, suppositories, solutions, suspensions, syrups or the like are also conceivable. In one embodiment the pharmaceutical composition according to the present invention contains NAC as the only active pharmaceutical ingredient. In addition such composition may contain a suitable carrier or excipient as described above.

The invention requires a strict assessment of the pharmaceutical quality of NAC

preparation for obtaining the effective dose. Therefore, brand or certified generic preparations have to be used. NAC is not a stable molecule, its active thiol residue can be easily oxidized by oxygen, light and other radiations, so that the effective dose would not be reached. The preparation is thus preferably protected from light, in soluble tablets, with sodium hydrogen carbonate, which helps in a partial removal of oxygen from water during dissolution.

It has been observed that high doses of NAC may cause abdominal pain. For overcoming this, an option is to provide NAC in a formulation with gastric protection, suitable for preventing NAC release/solubility in the stomach. Such formulations are well known in the art and may be used with the present invention. For example, tablet coatings that are resistant to gastric fluids and allow release of the drug only in the intestine, after its transit through the stomach, may be used. Commonly used formulations include polymers such as cellulose derivatives, methacrylate amino ester copolymers. The coating protects the tablet core from disintegration in the acidic environment of the stomach by employing a pH sensitive polymer, which swells or solubilises after having passed through the stomach, in response to an increase in pH, to release the drug.

Another option is to lower the dose of NAC entering the blood stream at any one time. Administration of NAC three or more times daily can be difficult to accomplish for the patient. Nevertheless, a repeated administration can be desirable to achieve a nearly constant serum concentration of NAC. To overcome these problems, an once or twice-a- day administration could be easier to handle for the patient, for instance morning and night. One option is to provide NAC in a slow-release formulation (also denoted sustained- release or controlled-release). By being able to reduce the rate of diffusion and uptake of NAC into the blood stream such a formulation enables administration of a larger dose at longer intervals. The dose is then distributed in the blood over a long time in small quantities, e.g. over 12+12 hours in the case of a twice-a-day regimen scheme. Many different technologies and formulations for slow-release are since long known in the art and may be applied with the present invention. In such technologies the active substance is for example encapsulated in a coating or matrix that is insoluble or less soluble in the body fluid where it is administered.

Formulations having a combined effect of slow-release and gastric protection are also possible and may be used within the present invention.

Use/medical indications of the present invention

The present invention has beneficial properties in relation to the treatment of patients suffering from dysmenorrhea, both primary and secondary dysmenorrhea. In particular it is beneficial for patients having primary dysmenorrhea, i.e. where there is no other underlying cause of the dysmenorrhea, such as disease or abnormal anatomy of the uterus or pelvic tract.

EXAMPLE: Clinical study on the effect of NAC for treatment of dysmenorrhea.

The invention will now be further described and illustrated by reference to the following non-limiting example.

MATERIAL AND METHODS

Patient enrolment: The study was performed on 21 patients suffering from primary dysmenorrhea who had been referred because of symptomatic pain treatment, see Table 1.

All of the patients complained of pain localized to the lower back (bilaterally) during menses. In 7 patients the pain began a day before menses, Inl6 patients the pain was colical and in the remaining 5 continuous. The intensity of the pain was so great that it compelled the patients to stay home from work. Also, 10 of the patients had to stay in bed for 2 days. All the patients who were included were examined by a gynaecologist and were informed of their diagnosis and asked if they wanted to take part in the trials.

Those willing to participate were informed about their role in the trial treatments.

Furthermore, the patients were told that they might or might not experience pain relief, or even exacerbated pain, but every effort was made to avoid any suggestion as to the effect. The patients were told that they could stop the trial treatment at any time. Their history of pain ranged from 18 months to 9 years. The mean age of the 21 patients was 22 years (15- 29). Measurement of pain: Before treatment, the patients were asked to describe the location of their pain and its characteristic qualities, using a modified McGill pain questionnaire. They were also asked to describe drug intake, intake of alcohol, smoking habits, physical activity levels, effects of the pain in relation to daily behaviour patterns and what made the pain increase or decrease. The patients also rated their subjective pain intensity before each stimulation session using a visual analogue scale. The words "no pain" and "worst pain ever" were placed at the left and right extreme end, respectively, of a 10 cm long horizontal line. The patients were instructed to mark the line at a point representing their pain. Results are shown in Table 1 and indicate the normal or ground value for each patient at menstruation, before the treatment sessions started. After stimulation, the patients were again asked to rate their median subjective pain intensity during the cycle period, which could be (see below). The normal or ground values were used for comparison in order to establish that the experienced pain was, before treatment, near normal.

Experimental protocol: The patients were randomly assigned to one of four groups, each group consisting of six patients. Three patients dropped out and were excluded. All patients were subjected to four modes of treatment, one at a time, each mode of treatment lasting for a separate menstrual cycle:

1. TNS/TENS: 30 mins x 2 daily (see further details below)

2. Naproxen: 500mg x 2 daily

3. Verapamil: 120mg x 2 daily

4. NAC: 15mg/kilo x 2 daily

Each treatment period starting when experiencing menses pain for the first time and until the end of the cycle/menses pain, which resulted in a total of 2- 5 days of treatment for each separate menstrual cycle and mode of treatment.

Following the end of the four different treatment cycles described above 7 patients were subjected to combinatorial treatment with NAC and one of the other treatment modes and were asked to rate the effect of a combination of NAC + Naproxen, TNS/TENS or Verapamil to elucidate if an additional effect would obtained.

High-frequency TNS/TENS The TNS/TENS apparatus used (Electroform 4C) produced monopolar square wave pulses with a duration of 0.2 msec and a frequency of 100 Hz. A pair of rubber electrodes, each with a surface area of 36 cm², were applied to the skin in the painful area. The stimulus intensity was just below the pain threshold (low intensity). At the treatment session, TNS/TENS was applied to the area of pain for 30 min.

RESULTS: The McGill pain questionnaire was used as a means of assessing the pain profile of patients suffering from dysmenorrhea. Factorial investigations of the

questionnaire provided for a distinction between affective and sensory descriptors

(dimensions). Forty-three per cent of the patients checked words (fearful, terrifying and wretched - blinding), describing emotional or affective aspects of the pain, which may reflect the negative attitude held by many women towards their period pains. Sixty-eight per cent of the patients checked sensory descriptors. Two components of sensory descriptors were derived - one related to dullness, and the other to cramping. In conclusion the pattern of scores emerging from the questionnaire indicates the significance of the emotional/affective aspect of the pain.

Pain intensity score

As stated in the Material and Methods section all patients were asked to rate their pre- treatment pain on a visual analogue scale. Thereafter the patients were asked to rate their pain when pain was experienced for the first time ("Before" in table 2) at a menstrual cycle and, after the end of the cycle period, to indicate their median/average cycle pain over the cycle ("After" in Table 2). As seen all modalities resulted in an alleviation of pain in most of the patients. Also, surprisingly, combining NAC with the other modalities showed a greater effect suggesting that NAC induces its pain alleviating effect through separate mechanisms.

Variable results of pain alleviation in response to drug treatment in dysmenorrhea have been reported, complicating its interpretation. Sources of variability are probably multi- factorial. Furthermore, factors such as operationalization of the outcome variable and the statistical method for evaluation could also be sources of variability. When pain is regarded as subjective, the produced data should be treated as ordinal. The rank-based method by Svensson, taking the non-metric qualities of the ordinal data into account as well as the variability at the group and the individual level, is therefore an alternative. To analyse the systematic patterns of change in assessed pain, indicating evidence of treatment on a group level, the relative position (RP) and relative concentration (RC), were measured. The variation related to the individual, the relative rank variation (RV) was also measured (data not shown).

It was shown that there were changes in RP and RC following each treatment suggesting that all treatments may have a pain alleviating effect at the group level. The individual variation was apparent suggesting that some patients respond better to one treatment than to another. Interestingly, combining treatments with NAC resulted in a change in RP and RV suggesting that NAC may potentiate the effect of TNS, NSAIDs and Verapamil in the treatment of dysmenorrhea.

Claims

1. A pharmaceutical composition comprising N-acetyl-L-cysteine(NAC) in

combination with a second pharmaceutically active ingredient for use in the treatment of a mammal having dysmenorrhea, wherein the composition is for oral administration at a dose of between 20 and 90 mg/kg/day of NAC .

2. A pharmaceutical composition comprising N-acetyl-L-cysteine in combination with a second pharmaceutically active ingredient for use according to the previous claim, wherein the composition is for oral administration at a dose of between 30 and 60 mg/kg/day of NAC.

A pharmaceutical composition comprising N-acetyl-L-cysteine in combination with a second pharmaceutically active ingredient for use according to any of the previous claims, wherein the composition is for oral administration at a dose of between 30 and 45 mg/kg/day of NAC.

A pharmaceutical composition comprising N-acetyl-L-cysteine for use according the previous claim, wherein the dysmenorrhea is primary dysmenorrhea.

A pharmaceutical composition comprising N-acetyl-L-cysteine for use according any of the previous claims, wherein the mammal does not have endometriosis.

A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claim 1, wherein the second pharmaceutically active ingredient is a non-steroidal anti-inflammatory drug (NSAID) such as naproxen.

7. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claim 1, wherein the second pharmaceutically active ingredient is a Ca²⁺ antagonist agent/calcium channel blocker such as verapamil.

8. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claim 1, wherein the second pharmaceutically active ingredient is replaced by non- pharmaceutical method such as TNS/TENS.

9. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, characterized in that it is protected from light.

10. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, characterized in that it is a water soluble tablet.

11. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according any of the previous claims, characterized in that it contains sodium hydrogen carbonate.

12. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to claims 1-5, characterized in that it comprises a formulation for slow-release and/or gastric protection.

13. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, wherein the mammal is a human.

14. A pharmaceutical composition comprising N-acetyl-L-cysteine for use according to any of the previous claims, wherein the treatment and/or the second treatment is for reducing pain in a mammal having dysmenorrhea.

15. A method for the treatment of a mammal having dysmenorrhea, comprising

administering a pharmaceutical composition comprising N-acetyl-L-cysteine according to any of the previous claims to said mammal.