Critical View on the Usage of Ribavirin in Already Existing Psychostimulant-Use Disorder

Substance-use disorder represents a frequently hidden non-communicable chronic disease. Patients with intravenous drug addiction are at high risk of direct exposure to a variety of viral infections and are considered to be the largest subpopulation infected with the hepatitis C virus. Ribavirin is a synthetic nucleoside analog that has been used as an integral component of hepatitis C therapy. However, ribavirin medication is quite often associated with pronounced psychiatric adverse effects. It is not well understood to what extent ribavirin per se contributes to changes in drug-related neurobehavioral disturbances, especially in the case of psychostimulant drugs, such as amphetamine. It is now well-known that repeated amphetamine usage produces psychosis in humans and behavioral sensitization in animals. On the other hand, ribavirin has an affinity for adenosine A1 receptors that antagonistically modulate the activity of dopamine D1 receptors, which play a critical role in the development of behavioral sensitization. This review will focus on the current knowledge of neurochemical/ neurobiological changes that exist in the psychostimulant drug-addicted brain itself and the antipsychotic-like efficiency of adenosine agonists. Particular attention will be paid to the potential side effects of ribavirin therapy, and the opportunities and challenges related to its application in already existing psychostimulant-use disorder.

Adenosine Receptor Agonists

Adenosine is a purine nucleoside that binds to adenosine cell surface receptors, which are widely expressed in heart and blood vessel cells as well as in the brain, kidney and adipose tissue.There are 4 subtypes of P1 (adenosine) G protein-coupled receptors (GPCR), named A1, A2A, A2B, and A3, which mediate a variety of cardioprotective and regenerative effects. In the heart, these effects are predominantly mediated through A1 receptors (A1R), which are expressed in atrial and ventricular cardiomyocytes and smooth muscle cells. Pre-clinical studies have reported multiple potential benefits achievable by modulation of adenyl cyclase with beneficial effects in a variety of pre-clinical models of cardiovascular disease including chronic heart failure (HF). A1R blockade (e.g. rolofylline) was however not successful in the PROTECT trial, where 2033 patients with acute HF and renal dysfunction were randomized to rolofylline or placebo, showed no benefit on renal function, symptoms, rehospitalization, or mortality. Following this attention turned to partial adenosine agonists, capadenoson and neladenoson bialanate hydrochloride, which has two phase II studies underway, PANACHE (HFpEF) and PANTHEON (HFrEF).

Adenosine receptor agonists differentially affect the anticonvulsant action of carbamazepine and valproate against maximal electroshock test-induced seizures in mice

SummaryBackground.Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.Aim.To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.Methods.The following adenosine receptor agonists were used: A1– cyclohexyladenosine, A2A– CGS 21 680, A3– N6-benzyl-NECA and A1(preferentially) and A2– 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1and A2antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.Results.Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).Conclusion.The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.

Bipolar affective disorder: A review of novel forms of therapy

Normothymic, antidepressant and antipsychotic pharmaceutics are, in accordance with international guidelines, employed both in the therapy and the prevention of bipolar disorder (BD). Long-term studies on the mechanisms of action of such medications, as well as on the pathogenetic background of BD, have led to the discovery of effective, albeit unconventional pharmacotherapeutic approaches. These methods have the potential to successfully treat mania and depression, as well as to counter affective episode relapse. Allopurinol - commonly used to treat gout, secondary hyperuricemia and Lesch-Nyhan syndrome, acts by inhibiting the synthesis of uric acid, levels of which are often increased in manic patients. Due to this, an evaluation of the potential effect of allopurinol on the reduction of mania symptoms seems to be reasonable. Additionally, the numerable research papers coming out of research regarding the role of purine neurotransmitters in mood alterations, indicate that adenosine agonists act analogously to dopamine antagonists. N-acetylcysteine (NAC), a supporting agent in the pharmacotherapy of depressive episodes in bipolar disorder, substantially accelerates mood stabilization in patients. In turn, memantine, known for its procognitive effect, not only has antimanic and normothymic properties, but also boosts the neuroprotective action of traditional lithium therapy. In view of the latest opinions, the subtle pro-inflammatory process is typical for the pathophysiology of bipolar disease. Acetylsalicylic acid (ASA) (a popular analgesic, antipyretic and antiphlogistic agent) may be useful in BD therapy. This is because that, via its effect upon cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), ASA modulates leukocyte recruitment in neuro-inflammation. Apart from the above-mentioned medications, this article introduces the results of recent investigations of ketamine, modafinil and tamoxifen, including their receptor mechanisms, as well as certain genetic aspects or elements of their pharmacodynamics, for use in BD therapy. We put forward that, possibly, more insightful cognition of these drugs will allow significant enrichment in the range of pharmacotherapy for BD in the near future.