Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy

Pecikoza, Uroš; Tomić, Maja; Nastić, Katarina; Micov, Ana; Stepanović-Petrović, Radica

doi:10.1016/j.biopha.2022.113441

Cited by 5 publications

(5 citation statements)

References 45 publications

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“…Moreover, combination of 2 substances permit to lower the dose of each drug, thus reducing the frequency of dose-dependent side effects [15,23,24]. However, even though there are various studies which examined the effect of specific drug combinations on diabetic neuropathy [19][20][21][22][24][25][26][27], the current study is the first to examine the combined effect of sildenafil and metformin on this condition. Regarding the specific mechanisms by which these two drugs might have an antihyperalgesic effect, it is worth mentioning that metformin, an antihyperglycemic agent recommended as first line therapy in type-2 diabetes according to the American Diabetes Association and the European Association for the Study of Diabetes [28], demonstrated its ability to ameliorate pain through different mechanisms.…”

Section: Musyc Algorithm Implementationmentioning

confidence: 95%

“…The method has the advantage of quantifying the synergism by several indicators and allowing a less biased and error prone assessment when compared to the classical methods [16,18]. It is worth mentioning that various studies have examined the synergistic effects of different substances (such as gabapentin, carbamazepine, duloxetine, amitriptyline, metformin, paracetamol, vitamin B12) in neuropathic pain in rats or mice, the vast majority of these studies relied in the synergy evaluation on classical methods (such as isobolographic analysis, mean effect difference or area under the curve) [19][20][21][22]24]. Hence, some of the mentioned studies might had underestimated or overestimated the synergistic effect, especially considering the fact that methods which assume additive dose-effect relationships (e.g.…”

Section: Musyc Algorithm Implementationmentioning

confidence: 99%

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Evaluating the Synergism Between Sildenafil and Metformin in an Animal Model of Diabetic Neuropathy Induced by Alloxan

PUȘCAȘU

2023

FARMACIA

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Given the complex mechanism of diabetic neuropathy, evaluating the effect of drug combinations in this pathology is of an utmost importance. The aim of this study was to evaluate the synergism between sildenafil and metformin in an alloxan induced diabetic neuropathy mouse model. The pain latency times obtained for male mice in the cold and heat hypersensitivity tests, as well as the administered drug doses were processed and analysed in Python Programming Language by using the Multidimensional Synergy of Combinations algorithm, with the computation of three drug synergy indicator types, based on efficacy, potency and cooperativity. The results showed mixed values in terms of the synergism and antagonism between sildenafil and metformin on neuropathic pain, but drug synergy was identified for at least one indicator for all experimental tests. While this study is the first to evaluate the synergism between sildenafil and metformin on diabetic neuropathy, future studies must aim in analysing a higher number of drug doses, with the development of a model which might be translated to clinical data. RezumatȚinând cont de mecanismul complex de declanșare a neuropatiei diabetice, este extrem de importantă evaluarea efectului combinațiilor medicamentoase în tratarea acestei patologii. Astfel, obiectivul principal al acestui studiu a fost reprezentat de evaluarea sinergismului dintre sildenafil și metformin într-un model animal de neuropatie diabetică indusă de aloxan. Timpii obținuți pentru șoareci masculi în cadrul testelor de hipersensibilitate termică (la rece, respectiv la cald), precum și dozele administrate din cele două medicamente au fost analizate în cadrul limbajului de programare Python pe baza unui algoritm de evaluare a sinergismului (Sinergismul multidimensional al combinațiilor medicamentoase), cu obținerea a trei tipuri de indicatori de sinergism: eficacitatea, potența și cooperativitatea. Rezultatele obținute au indicat valori mixte în privința sinergismului și antagonismului dintre sildenafil și metformin, dar sinergismul medicamentos a fost identificat pentru cel puțin un tip de indicator pentru toate testele experimentale. În concluzie, studiul actual este primul care evaluează sinergismul dintre sildenafil și metformin în neuropatia diabetică. În cadrul unor studii viitoare, este necesară evaluarea mai multor doze de medicament, cu obținerea unui model care să poată fi aplicat și în cazul datelor clinice.

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Section: Musyc Algorithm Implementationmentioning

confidence: 95%

Section: Musyc Algorithm Implementationmentioning

confidence: 99%

Evaluating the Synergism Between Sildenafil and Metformin in an Animal Model of Diabetic Neuropathy Induced by Alloxan

PUȘCAȘU

2023

FARMACIA

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“…The diabetic animals, with blood glucose values ≥180 mg/dL, were selected for further testing. If the blood sugar was lower than 180 mg/dL, the mice received one or two doses of alloxan (150 mg·kg −1 i.p., at 48 h intervals) and were selected if they became diabetic [ 26 , 30 ]. The determination was made in the morning at 8:00 AM under fasting conditions for 24 h before the determination.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, the results of several studies highlighted that combined therapy is a more efficient option to treat chronic diseases with complex etiology and pathophysiology such as diabetes, cancer, or AIDS [ 27 , 28 , 29 ]. Current guidelines recommend, in the majority of situations, monotherapy in diabetic neuropathy, but the efficacy and safety are frequently limited [ 30 , 31 ]. As a consequence, the therapeutic approach to diabetic neuropathy with a combination of two drugs that ameliorate pain through different mechanisms of action could be a better option and could overcome these limitations.…”

Section: Introductionmentioning

confidence: 99%

The Influence of Sildenafil–Metformin Combination on Hyperalgesia and Biochemical Markers in Diabetic Neuropathy in Mice

Pușcașu,

Ungurianu,

Șeremet

et al. 2023

Medicina

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Background and objectives: Worldwide, approximately 500 million people suffer from diabetes and at least 50% of these people develop neuropathy. Currently, therapeutic strategies for reducing diabetic neuropathy (DN)-associated pain are limited and have several side effects. The purpose of the study was to evaluate the antihyperalgesic action of different sildenafil (phosphodiesterase-5 inhibitor) and metformin (antihyperglycemic agent) combinations in alloxan-induced DN. Methods: The study included 100 diabetic mice and 20 non-diabetic mice that were subjected to hot and cold stimulus tests. Furthermore, we determined the influence of this combination on TNF-α, IL-6 and nitrites levels in brain and liver tissues. Results: In both the hot-plate and tail withdrawal test, all sildenafil–metformin combinations administered in our study showed a significant increase in pain reaction latencies when compared to the diabetic control group. Furthermore, all combinations decreased blood glucose levels due to the hypoglycemic effect of metformin. Additionally, changes in nitrite levels and pro-inflammatory cytokines (TNF-α and IL-6) were observed after 14 days of treatment with different sildenafil–metformin combinations. Conclusions: The combination of these two substances increased the pain reaction latency of diabetic animals in a dose-dependent manner. Moreover, all sildenafil–metformin combinations significantly reduced the concentration of nitrites in the brain and liver, which are final products formed under the action of iNOS.

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“…Pecikoza et al examined the interaction of the hypoglycemic drug metformin and duloxetine/oxycodone/eslicarbazepine acetate/vitamin B12 in relieving pain hypersensitivity in diabetes. The combination of metformin and these analgesics or vitamin B12 can be more effective in relieving pain and reducing the vitamin B12 deficiency caused by metformin [ 24 ]. Bedair investigated the therapeutic effect of the analgesic morphine combined with the association of tennis professionals-sensitive potassium channel opener nicodil in the rat model of hepatic fibrosis pain, revealing that this treatment strategy could significantly enhance pain resistance and have a significant hepatoprotective effect.…”

Section: Definition and Classification Of Pain And The Common Drugs U...mentioning

confidence: 99%

Nanomaterial-Based Drug Delivery Systems for Pain Treatment and Relief: From the Delivery of a Single Drug to Co-Delivery of Multiple Therapeutics

Xu,

Dong,

et al. 2023

Pharmaceutics

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The use of nanomaterials in drug delivery systems for pain treatment is becoming increasingly common. This review aims to summarize how nanomaterial-based drug delivery systems can be used to effectively treat and relieve pain, whether via the delivery of a single drug or a combination of multiple therapeutics. By utilizing nanoformulations, the solubility of analgesics can be increased. Meanwhile, controlled drug release and targeted delivery can be realized. These not only improve the pharmacokinetics and biodistribution of analgesics but also lead to improved pain relief effects with fewer side effects. Additionally, combination therapy is frequently applied to anesthesia and analgesia. The co-encapsulation of multiple therapeutics into a single nanoformulation for drug co-delivery has garnered significant interest. Numerous approaches using nanoformulation-based combination therapy have been developed and evaluated for pain management. These methods offer prolonged analgesic effects and reduced administration frequency by harnessing the synergy and co-action of multiple targets. However, it is important to note that these nanomaterial-based pain treatment methods are still in the exploratory stage and require further research to be effectively translated into clinical practice.

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Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy

Cited by 5 publications

References 45 publications

Evaluating the Synergism Between Sildenafil and Metformin in an Animal Model of Diabetic Neuropathy Induced by Alloxan

Evaluating the Synergism Between Sildenafil and Metformin in an Animal Model of Diabetic Neuropathy Induced by Alloxan

The Influence of Sildenafil–Metformin Combination on Hyperalgesia and Biochemical Markers in Diabetic Neuropathy in Mice

Nanomaterial-Based Drug Delivery Systems for Pain Treatment and Relief: From the Delivery of a Single Drug to Co-Delivery of Multiple Therapeutics

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