**7. Future perspectives**

Taking into account that the UPS controls important functions in eukaryotic cell, proteasome inhibitors could have been considered as toxins without any therapeutic value. Unexpectedly, proteasome inhibitors are well-tolerated drugs and do not produce adverse effects in normal cells even at high doses. Though, clinical trials indicate that use of bortezomib induces peripheral sensory neuropathy in patients, which might limit its therapeutic use. However, the reversible proteasome inhibitor such as MG132 apparently did not produce any toxic effect and was well tolerated. The use of reversible proteasome inhibitors can therefore be considered as a better alternative. It will be a future challenge to develop drugs specifically targeting the UPS, or more specifically UPS E3 ligases that select proteins for the UPS-mediated degradation, in order to treat inflammatory joint disorders. Non-toxic proteasome inhibitors alone and/or in combination with conventional RA therapies might be more effective to treat patients with this painful and debilitating arthritic disease.

### **8. References**

148 Rheumatoid Arthritis – Treatment

peripheral inflammation induces a dramatic up-regulation of PDYN biosynthesis in nociceptive neurons of the spinal dorsal horn (Przewlocki, 1987; Marvizon et al., 2009). As a future perspective it will be interesting to observe the effects of proteasome inhibition in the DRG and SC in inflammation. In the monosodium-induced model of osteoarthritis, which is a well-recognized model of osteoarthritis, MG132 treatment has normalized the upregulated expression of SP and CGRP in the inflamed knee joints and their corresponding

The clinical application of proteasome inhibitors might be limited due to potential side effects of available compounds following chronic administration. Toxic affects might result from the accumulation of ubiquitinated proteins after inhibition of the 26S proteasome. The proteasome inhibitor bortezomib (PS-341) induced mild-to-moderate neurotoxic effects in rats [Cavaletti et al., 2007] and peripheral sensory neuropathy in cancer patients when given this compound chronically [Cata et al., 2006]. The features of bortezomib neuropathy are characteristic for a small fiber neuropathy and are characterized by a more sensory than motor neuropathy. Several observations, however, argue against these possibilities. First, in rats, the neurotoxic effects were observed when bortezomib was administered at maximum tolerated, sub-lethal doses in rats [Cavaletti et al., 2007]. Bortezomib might have induced neurotoxic effects because of the presence of a component in its activity that is blocked by the polyhydroxyl compound Tiron, this component is not involved in MG132 activity [Fernandez et al., 2006]. No effects of MG132 toxicity were apparent on motor performance during rotarod, posture, gait, exploratory and locomotor activity, or on cell death in the spinal cord, when MG132 was administered at higher doses [Ossipov et al., 2006]. Moreover, MG132 treated animals gained significantly more body weight than the vehicle treated arthritic controls [Ahmed et al., 2010]. These results indicate that proteasome inhibitor MG132 given at therapeutically relevant doses was well tolerated. This is a significant finding as the proteasome plays a central role in many intracellular functions and its

DRG, with reduced pain behavior [Ahmed et al, unpublished data]**.** 

inhibition might theoretically be expected to induce numerous side effects.

Taking into account that the UPS controls important functions in eukaryotic cell, proteasome inhibitors could have been considered as toxins without any therapeutic value. Unexpectedly, proteasome inhibitors are well-tolerated drugs and do not produce adverse effects in normal cells even at high doses. Though, clinical trials indicate that use of bortezomib induces peripheral sensory neuropathy in patients, which might limit its therapeutic use. However, the reversible proteasome inhibitor such as MG132 apparently did not produce any toxic effect and was well tolerated. The use of reversible proteasome inhibitors can therefore be considered as a better alternative. It will be a future challenge to develop drugs specifically targeting the UPS, or more specifically UPS E3 ligases that select proteins for the UPS-mediated degradation, in order to treat inflammatory joint disorders. Non-toxic proteasome inhibitors alone and/or in combination with conventional RA therapies might be more effective to treat patients with this painful and

**6. Toxicity** 

**7. Future perspectives** 

debilitating arthritic disease.


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**8** 

**Enkorten – A Potential Drug for the Treatment of Rheumatoid Arthritis**

*Medical Faculty University of Sarajevo Institute of Pharmacology,* 

Enkorten is a new potential drug for the treatment of rheumatoid arthritis**,** with an immunomodulatory and anti-inflammatory effect. It is a combination of two peptide components of endogenous origin: methionine-enkephalin of 5 mg and tridecactide of 1 mg (Picture 1 and 2). According to the chemical structures, these components correspond to

Amino acid sequence: H-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-OH

The holder of effects of the tested combination is alpha 1-13 corticotrophin–tridecactide (ACTH 1-13), composed of 13 amino acids, identical to the amino acid sequence of the alpha-melanostimulating hormone (-MSH), but without the acetyl and amide ending. Some studies suggest that -MSH is synthesized in the pituitary, other parts of the CNS, the placenta, and some endocrine organs – especially the adrenal, the skin and the gastrointestinal tract (Star et al, 1995; Catania et al, 2000). The presence of this neuropeptide in the mucous membrane of the gastrointestinal tract and keratinocytes of the skin suggests

Jasna Kusturica, Maida Todić-Rakanović, Mirjana Mijanović, Fahir Bečić, Asija Začiragić,

*Medical Faculty University of Sarajevo Institute of Pharmacology, Clinical Pharmacology and Toxicology,* 

Selma Škrbo, Lejla Burnazović-Ristić, Aida Kulo and Svjetlana Loga-Zec

amino acid sequences of the neuropeptide precursor proopiomelanocortin.

Chemical name: (des-acetyl)--MSH-(de-amid) - -MSH

Generic name: met-enkephalin 1-5 adrenorphin

Amino acid sequence: H-Tyr-Gly-Gly-Phe-Met-OH Picture 2. Chemical characteristics of met-enkephalin

**1. Introduction** 

 \*

*Bosnia and Herzegovina*

Generic name: tridecactide

Molecular weight: 1623.85

Gross formula: C75H106N20O19S

Gross formula: C27H35N5O7S Molecular weight: 573.67

Picture 1. Chemical characteristics of tridecactide

Nedžad Mulabegović et al.\*

*Bosnia and Herzegovina* 

*Clinical Pharmacology and Toxicology* 

Zwerina J, Hayer S, Tohidast-Akrad M, Bergmeister H, Redlich K, Feige U, et al. Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. Arthritis Rheum. 2004;50(1):277-90.
