Combinations Of Nonsteroidal Anti-inflammatory Drugs Research Articles

Postoperative Complications Associated with Non-Steroidal Anti-Inflammatory Combinations Used Status-Post Total Hip and Knee Arthroplasty.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in multimodal pain control following total joint arthroplasty (TJA). However, few studies have assessed the complications associated with the combinations of NSAIDs in this population despite the known risks associated with this class of medications. The Premier Healthcare Database was queried to identify adults who underwent primary total hip or knee arthroplasty from 2005-2014. The following most common inpatient combinations of NSAIDs were chosen for analysis: aspirin + celecoxib (A + C), toradol + aspirin (T + A), toradol + ibuprofen (T + I), celecoxib + ibuprofen (C + I), ibuprofen + aspirin (I + A), and toradol + celecoxib (T + C). Primary outcomes included acute kidney injury (AKI), gastrointestinal bleed, and stroke. Secondary outcomes included periprosthetic joint infection (PJI), deep vein thrombosis, and pulmonary embolism. Univariate and multivariate regression analyses were used to compare differences and address confounds. Overall, 195,833 patients were identified. After controlling for confounds, increased odds of AKI was associated with A + C (adjusted odds ratio [aOR]: 1.20, 95% confidence interval [CI]: 1.09-1.34, p < 0.001) and decreased odds was associated with T + A (aOR 0.76, 95% CI: 0.69-0.83, p < 0.001). Increased odds of stroke was associated with A + C (aOR: 1.80, 95% CI: 1.15-2.84, p = 0.011); T + I (aOR 3.48, 95% CI: 1.25-9.73, p = 0.017); and I + A (aOR 4.29, 95% CI: 1.06-17.9, p = 0.046). Increased odds of PJI was associated with C + I (aOR: 10.3, 95% CI: 1.35-78.3, p = 0.024). In the TJA patient population, NSAID pairings should be regarded as distinct entities. Our results suggest that combinations including A + C, T + I, I + A, and C + I should be used cautiously. With this knowledge, providers should consider tailoring NSAID prescriptions appropriately.

Parenteral Ready-to-Use Fixed-Dose Combinations Including NSAIDs with Paracetamol or Metamizole for Multimodal Analgesia-Approved Products and Challenges.

The combination of non-steroidal anti-inflammatory drugs (NSAIDs) with non-opioid analgesics is common in clinical practice for the treatment of acute painful conditions like post-operative and post-traumatic pain. Despite the satisfactory results achieved by oral analgesics, parenteral analgesia remains a key tool in the treatment of painful conditions when the enteral routes of administration are inconvenient. Parenteral ready-to-use fixed-dose combinations of non-opioid analgesics combinations, including NSAIDs and paracetamol or metamizole, could play a central role in the treatment of painful conditions by combining the advantages of multimodal and parenteral analgesia in a single formulation. Surprisingly, only in 2020, a parenteral ready-to-use fixed-dose combination of ibuprofen/paracetamol was launched to the market. This review aims to investigate the current availability of combinations of NSAIDs with paracetamol or metamizole in both European and American markets, and how the combination of such drugs could play a central role in a multimodal analgesia strategy. Also, we explored how the parenteral formulations of NSAIDs, paracetamol, and metamizole could serve as starting elements for the development of new parenteral ready-to-use fixed-dose combinations. We concluded that, despite the well-recognized utility of combining NSAIDs with paracetamol or metamizole, several randomized clinical trial studies demonstrate no clear advantages concerning their efficacy and safety. Future clinical trials specifically designed to assess the efficacy and safety of pre-formulated fixed-dose combinations are required to generate solid evidence about their clinical advantages.

Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects.

Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments.

Reversal of itraconazole resistance in Sporothrix brasiliensis and Sporothrix schenckii by nonsteroidal anti-inflammatory drugs

BackgroundThe emergence of resistant isolates has brought challenges to the treatment of sporotrichosis, prompting the search for new therapeutic strategies. Previous studies reported that nonsteroidal anti-inflammatory drugs (NSAIDs) show in vitro activity against several pathogenic fungi, including species of Candida, Cryptococcus, and Trichosporon. AimsThis study aimed to investigate the in vitro efficacy of three NSAIDs (acetylsalicylic acid, diclofenac sodium, and ibuprofen), alone and in combination with itraconazole, against eleven clinical isolates of Sporothrix brasiliensis and Sporothrix schenckii. MethodsMinimal inhibitory concentrations were determined by the broth microdilution method. Drug interactions and the fractional inhibitory concentration index of NSAIDs and itraconazole were assessed by the checkerboard method. ResultsWhen used alone, ibuprofen was the most active NSAID, followed by acetylsalicylic acid. Combinations of NSAIDs with itraconazole showed synergistic antifungal activity against nine isolates. It was also found that itraconazole combined with acetylsalicylic acid, diclofenac sodium, or ibuprofen, led to resistance reversal in two, three, and five of the six drug-resistant isolates, respectively. ConclusionsThe results indicate that the combination of itraconazole and the evaluated NSAIDs are a promising strategy for the treatment of sporotrichosis.

Risk of Major Adverse Cardiovascular Events Associated with Concomitant Use of Antidepressants and Non-steroidal Anti-inflammatory Drugs: A Retrospective Cohort Study.

Both antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to affect platelet aggregation, blood pressure and heart rate. Despite the high prevalence of the combined use of antidepressants and NSAIDs, there is limited evidence on the potential risk of major adverse cardiovascular events (MACE) associated with their use. The objective of this study was to assess the association between concomitant antidepressant and NSAID use and MACE. We conducted a retrospective cohort study using South Korea's nationwide healthcare database. The study cohort was defined as those with new prescriptions for antidepressants and NSAIDs between 2004 and 2015. Exposure was assessed as time varying into four discrete periods: non-use, antidepressant use, NSAID use and concomitant use. Our primary outcome was MACE, a composite of haemorrhagic and thromboembolic events; secondary outcomes were the individual events of MACE. A multivariable Cox proportional hazards model was used to estimate hazards ratios with 95% confidence intervals. We also performed subgroup analyses by class of antidepressant/type of NSAIDs, age and sex. From 240,982 patients, 235,080, 4393 and 1509 patients were users of NSAIDs, antidepressants or both drugs at cohort entry, respectively. The cohort generated 2.1 million person-years of follow-up with 22,453 events of MACE (incidence rate 1.07 per 100 person-years). Compared with non-use, concomitant use (hazard ratio 1.13, 95% confidence interval 1.01-1.26) and NSAID-only use (1.05, 1.001-1.10) were positively associated with MACE, while antidepressant-only use showed a negative association (0.91, 0.83-0.99). Concomitant use increased the individual risk of haemorrhagic stroke (1.46, 1.06-2.00), ischaemic stroke (1.22, 1.07-1.38) and heart failure (1.19, 1.02-1.38), but showed a protective effect on cardiovascular deaths (0.36, 0.21-0.62). Of the six possible combinations of antidepressants and NSAIDs by their classes, only concomitant use of tricyclic antidepressants and non-selective NSAIDs was positively associated with MACE (1.26, 1.09-1.47). The risk of MACE remained elevated with concomitant use among those aged ≥ 45years (1.14, 1.01-1.29) and male patients (1.19, 1.01-1.42). Concomitant use of antidepressants and NSAIDs moderately elevated the risk of MACE, of which the observed risk appears to be driven by the concomitant use of tricyclic antidepressants and non-selective NSAIDs. Thus, healthcare providers should take precaution when co-prescribing these drugs, weighing the potential benefits and risks associated with their use.

Antibiotic susceptibility profile and synergistic effect of non-steroidal anti-inflammatory drugs on antibacterial activity of resistant antibiotics (Oxytetracycline and Gentamicin) against methicillin resistant Staphylococcus aureus (MRSA)

Non-steroidal anti-inflammatory drugs (NSAIDs) may exhibit antibacterial activity and have synergistic effects with antibiotics. One way to re-sensitize MRSA to resistant antibiotics is by combining with approved non-antibiotics. The study was intended to explore susceptibility of MRSA to various antibiotics and non-antibiotics (NSAIDs) by micro dilution broth method. MRSA isolates were confirmed by PCR (mecA gene) and in-vitro antibiotic susceptibility was determined by disc diffusion tests. Combinations of NSAIDs with resistant antibiotics were also evaluated in in-vivo trial in mice. In-vitro antibiotic susceptibility profile presented 100% resistance to Cefoxitin, 37.5% to Gentamicin and Amikacin, 25% to Oxytetracycline, 12.5% to Tylosin, Fusidic acid and Vancomycin, while Ciprofloxacin, Levofloxacin, Moxifloxacin, Trimethoprim + Sulfamethoxazole and Linezolid were found sensitive. Synergistic effect was observed when resistant antibiotics (Oxytetracycline/Gentamicin) were combined with sensitive antibiotics (Ciprofloxacin/Linezolid). Combination of Non-antibiotics (NSAIDs) with resistant antibiotics revealed that Meloxicam showed partial synergism with both Oxytetracycline and Gentamicin, while Flunixin Meglumine presented synergistic effect with Oxytetracycline and partial synergism with Gentamicin. Diclofenac Sodium revealed additive effect with Oxytetracycline while in case of Gentamicin indifferent effect was observed. In-vivo results showed that combinations of Oxytetracycline with Meloxicam/Flunixin Meglumine and Gentamicin with Meloxicam/Flunixin Meglumine were effective. The study concluded that the resistance against milk borne zoonotic MRSA infections can be successfully addressed by combining resistant antibiotics with NSAIDs. Flunixin Meglumine can be used in combination with oxytetracycline against MRSA infection.

DIAGNOSIS DAN TATALAKSANA KOMPREHENSIF OSTEOARTRITIS

DIAGNOSIS DAN TATALAKSANA KOMPREHENSIF OSTEOARTRITIS

Differential chemoreactome analysis of synergistic combinations of tolperisone and nonsteroidal anti-inflammatory drugs

The concurrent use of muscle relaxants and nonsteroidal anti-inflammatory drugs (NSAIDs) is a promising treatment for painful muscle hypertonia and convulsive states.Objective: to identify the most effective and safe synergist combinations of tolperisone and NSAIDs.Material and methods. A differential chemoreactome analysis was employed to evaluate the effects of the muscle relaxant tolperisone and five NSAIDs (dexketoprofen, etoricoxib, meloxicam, naproxen, and diclofenac). The biological activities of the molecules under study were assessed in five sections: 1) inhibition of the proteins of prostaglandin and leukotriene metabolism; 2) inhibition of the effects of the transcription factor nuclear factor kappa, tumor necrosis factor-, and other anti-inflammatory mechanisms; 3) inhibition of excessive blood coagulation and platelet aggregation; 4) vasodynamic effects; 5) antitumor properties on cell lines in culture.Results and discussion. Based on the differences in the pharmacological activity profiles of tolperisone and NSAIDs under study, the investigators identified the most promising synergistic combinations, in which both active ingredients complemented each other as effectively and safely as possible. The obtained estimates of the degree of synergism of various combinations of tolperisone and NSAIDs hold that the most promising antithrombotic, and antitumor effects.Conclusion. The results of this study will help adequately choose combinations of muscle relaxants and NSAIDs in patients with muscle hypertonia, which will be able to improve the efficiency and safety of treatment.

ПЕРСПЕКТИВЫ ИСПОЛЬЗОВАНИЯ КОМБИНАЦИИ ЛОКАЛЬНО ВВОДИМЫХ НЕСТЕРОИДНЫХ ПРОТИВОВОСПАЛИТЕЛЬНЫХ СРЕДСТВ И ОПИОИДОВ В ЛЕЧЕНИИ БОЛИ ПЕРИФЕРИЧЕСКОГО ГЕНЕЗА

The article reviews scientific literature on serious side effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics widely used to treat acute and chronic pain. In order to reduce the incidence of side effects in clinical practice, oral combinations of NSAIDs and opioids are used. Unfortunately, the efficacy and safety of these combinations also do not meet contemporary requirements for analgesics. Local use of NSAIDs and opioids is one of the alternatives, which will reduce the dose of systemically administered drugs. Peripheral mechanisms play a key role in systemic mu-opioid analgesia. The use of these mechanisms when developing medication for pain relief offers promising prospects in the treatment of acute and chronic pain.

Differential chemoreactome analysis of glucosamine sulfate and non-steroidal anti-inflammatory drugs: promising synergistic drug combinations

Glucosamine sulfate (GS) is essential for the regeneration of cartilaginous tissue and, in addition, it has anti-inflammatory properties comparable to those of nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical trials indicate the synergism between GS and NSAIDs in osteoarthritis (OA) and other joint diseases. Objective : to estimate the degree of synergism between different combinations of GS and NSAIDs. Material and methods . A differential chemoreactome analysis was employed to evaluate the effects of GS and seven agents from the class of NSAIDs, such as ketorolac, nimesulide, diclofenac, meloxicam, dexketoprofen, celecoxib, and etoricoxib, for estimating the degree of synergism between different combinations of GS and NSAIDs. Results and discussion . Dexketoprofen is shown to enhance most effectively the anti-inflammatory properties of GS as compared to ketorolac that does this to a lesser extent. The drug should be practically used as follows: the most effective combination (GS + dexketoprofen (or GS + ketorolak) is taken at week 1 of treatment for rapid pain elimination; thereafter there may be a combination of GS and NSAIDs, the intake of which is associated with minimal adverse reactions for a longer time. Conclusion . The investigation has shown that the coadministration of GS and NSAIDs is promising in treating joint diseases.

Evaluation of prescribing pattern and adverse effects of fixed dose combination of non-steroidal anti-inflammatory drugs

Background: The use of fixed does combination of drugs is a major controversial health related issue. The non-steroidal anti-inflammatory drugs (NSAIDs) is one of the most frequently use drugs in population. The present study was undertaken to observe the pattern of use fixed dose combinations of NSAIDs and its adverse effects. Methods: The study was approved by the institutional ethics committee. Randomly selected patients irrespective of age and sex, who were on NSAIDs from the indoor and outdoor patients of paediatric, medicine and orthopaedic departments, were included in the study. Patients with history of administration of NSAIDs in last 30 days kidney, liver, acid-peptic disease, pregnancy and lactation were excluded from the study. WHO causality assessment scale was used for adverse reactions occurred due to fixed dose combinations (FDCs) of NSAIDs. The preventability, severity of the adverse drug reactions (ADRs) was evaluated. Results: Total one thousand participants were included in the study, among them 112 had received analgesic FDCs. Diclofenac+paracetamol and ibuprofen+paracetamol were the highest used in the study. Maximum combinations were found in the age group 41-60 years, the second highest (37 combinations) were in age group of 19-40 years. Fourty-two ADRs were due to the use of FDCs of NSAIDS. It was found that nimesulide+paracetamol was culprit in causing ADRs in 60 percent and diclofenec+paracetamol was in 40 percent of the participants. GI related adverse reaction observed in 28 participants. It was found that eighty percent of the adverse reaction was possible in nature. Most of the ADRs were mild in nature. It was evident that majority of ADRs were definitely preventable. Conclusions: There is a wide use of analgesic FDCs which should be discouraged.

The experimental study of anti-inflammatory properties of the drug “Diclocor”

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used groups of medicines. Despite the undeniable clinical effectiveness, their use is associated with the risk of side effects. This fact directs scientific research to searching combinations of NSAIDs with other substances in order to identify compositions which will allow reducing the dose of the NSAID without losing its anti-inflammatory effectiveness. In view of all this, a new combined drug “Diclocor” developed by “Borshchahivskiy CPP” (Ukraine) is of interest. The article presents the results of the experimental study of the anti-inflammatory effect of the combined drug “Diclocor” in comparison with its active monocomponents – diclofenac sodium and quercetin. The alterative stage of inflammation was studied on the model of scarified wounds, the exudative stage – on the model of carrageenin edema, and the proliferative stage – on the model of cotton pellet-induced granuloma. All studies were conducted in rats. The experimental results have shown the superiority of Diclocor in influencing on all three stages of inflammation compared to the reference drugs in the appropriate doses. Diclocor has exhibited the most pronounced effect on the stages of alteration and exudation, and can be described as a promising drug for the treatment of proliferative and destructive inflammatory diseases.

Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin–angiotensin system inhibitors in the community increases the risk of acute kidney injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin-angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin-angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case-control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin-angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25-2.14)) and dual combinations with either renin-angiotensin system inhibitors (1.60 (1.18-2.17)) or diuretics (1.64 (1.17-2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin-angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin-angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.

Nonsteroidal Anti‐Inflammatory Drugs, Gastroprotection, and Benefit–Risk

BackgroundGastroprotective agents (GPA) substantially reduce morbidity and mortality with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin.ObjectiveTo evaluate efficacy of NSAIDs, protection against NSAID-induced gastrointestinal harm, and balance of benefit and risk.MethodsFree text searches of PubMed (December 2012) supplemented with “related citation” and “cited by” facilities on PubMed and Google Scholar for patient requirements, NSAID effectiveness, pain relief benefits, gastroprotective strategies, adherence to gastroprotection prescribing, and serious harm with NSAIDs and GPA.ResultsPatients want 50% reduction in pain intensity and improved fatigue, distress, and quality of life. Meta-analyses of NSAID trials in musculoskeletal conditions had bimodal responses with good pain relief or little. Number needed to treat (NNTs) for good pain relief were 3 to 9. Proton pump inhibitors (PPI) and high-dose histamine-2 receptor antagonists (H2RA) provided similar gastroprotection, with no conclusive evidence of greater PPI efficacy compared with high-dose H2RA. Prescriber adherence to guidance on use of GPA with NSAIDS was 49% in studies published since 2005; patient adherence was less than 100%. PPI use at higher doses over longer periods is associated with increased risk of serious adverse events, including fracture; no such evidence was found for H2RA. Patients with chronic conditions are more willing to accept risk of harm for successful treatment than their physicians.ConclusionGuidance on NSAIDs use should ensure that patients have a good level of pain relief and that gastroprotection is guaranteed for the NSAID delivering good pain relief. Fixed-dose combinations of NSAID plus GPA offer one solution.

Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs.

The injurious effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the small intestine was not appreciated until the widespread use of capsule endoscopy. Animal studies found that NSAID-induced small intestinal injury depends on the ability of these drugs to be secreted into the bile. Because the individual toxicity of amphiphilic bile acids and NSAIDs directly correlates with their interactions with phospholipid membranes, we propose that the presence of both NSAIDs and bile acids alters their individual physicochemical properties and enhances the disruptive effect on cell membranes and overall cytotoxicity. We utilized in vitro gastric AGS and intestinal IEC-6 cells and found that combinations of bile acid, deoxycholic acid (DC), taurodeoxycholic acid, glycodeoxycholic acid, and the NSAID indomethacin (Indo) significantly increased cell plasma membrane permeability and became more cytotoxic than these agents alone. We confirmed this finding by measuring liposome permeability and intramembrane packing in synthetic model membranes exposed to DC, Indo, or combinations of both agents. By measuring physicochemical parameters, such as fluorescence resonance energy transfer and membrane surface charge, we found that Indo associated with phosphatidylcholine and promoted the molecular aggregation of DC and potential formation of larger and isolated bile acid complexes within either biomembranes or bile acid-lipid mixed micelles, which leads to membrane disruption. In this study, we demonstrated increased cytotoxicity of combinations of bile acid and NSAID and provided a molecular mechanism for the observed toxicity. This mechanism potentially contributes to the NSAID-induced injury in the small bowel.

Evaluation of gastric tolerability, antinociceptive and antiinflammatory activity of combination NSAIDs in rats

Non-steroidal antiinflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs in clinical practice. Presently, several varieties of fixed dose combinations (FDCs) of NSAIDs are available over the counter and are being prescribed too. There is paucity of literature regarding comparative efficacy of these combinations against their individual component. Various clinical studies have documented increased incidence of gastric ulcerations with usage of more than one NSAID simultaneously. To study gastric tolerability, antinociceptive and antiinflammatory activity of combination NSAIDs in rats. Gastric tolerability of different NSAIDs was observed after administration of drugs for 7 days orally. On 7 th day, 4 h after drug administration, rats were sacrificed and stomach mucosa was examined for ulcerations. Analgesic or antinociceptive activity of single and combination NSAIDs was evaluated using Writhing test model. For induction of writhing, 4% normal saline (hypertonic saline) was injected (0.1 ml/10 gm) intraperitoneally. Evaluation of antiinflammatory activity for FDCs of NSAIDs was done by using rat paw edema model with the aid of plethysmometer. Paw edema was induced by injecting 0.1 ml of 1% formalin in sub-planter region of hind paw. Analgesic activity was found to be enhanced or significant only in the group pretreated with combination of nimesulide with ibuprofen as compared to ibuprofen-alone group (P = 0.01). Decrease in mean paw edema (antiinflammatory activity) was not significant in rats pretreated with combination NSAIDs as compared to NSAID-alone group. Mean gastric ulcer index was significant in groups pretreated with diclofenac alone (P = 0.03) and in combination groups of nimesulide with diclofenac and ibuprofen with paracetamol as compared to control (P = 0.03, P = 0.007). Addition of ibuprofen to paracetamol and combining diclofenac to nimesulide, significantly increased severity of gastric ulcerations. Fixed dose combination does not possess additional analgesic activity over their individual components, only exception being combination of nimesulide with ibuprofen, which has additional analgesic activity over ibuprofen alone, and this combination was not found to be ulcerogenic. Antiinflammatory activity of ibuprofen, paracetamol and nimesulide was significantly enhanced after addition of diclofenac.

Spinal synergy between nonselective cyclooxygenase inhibitors and morphine antinociception in mice

The antinociception induced by the intrathecal coadministration of combinations of morphine with the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen, piroxicam, metamizol, diclofenac and ketoprofen was studied by isobolographic analysis in the acetic acid writhing test of mice. The effective dose that produced 50% antinociception (ED 50) was calculated from the log dose–response curve of intrathecally administered fixed ratio combinations of morphine with each NSAID. By isobolographic analysis, this ED 50 was compared to the theoretical additive ED 50 calculated from the ED 50 of morphine and of each NSAID alone. As shown by isobolograms, all the combinations were synergistic, the experimental ED 50's being significantly smaller than the theoretically calculated ED 50's. The results of this study demonstrate potent interactions between morphine and NSAIDs and validate the clinical use of the combinations of opioids and NSAIDs in pain treatment, even by the intrathecal route.

Carbachol interactions with nonsteroidal anti-inflammatory drugs.

The inhibition of cyclooxygenase enzymes by nonsteroidal anti-inflammatory drugs (NSAIDs) does not completely explain the antinociceptive efficacy of these agents. It is known that cholinergic agonists are antinociceptive, and this study evaluates the interactions between carbachol and some NSAIDs. Antinociceptive activity was evaluated in mice by the acetic acid writhing test. Dose-response curves were constructed for NSAIDs and carbachol, administered either intraperitoneally (i.p.) or intrathecally (i.t.). The interactions of carbachol with NSAIDs were evaluated by isobolographic analysis after the simultaneous administration of fixed proportions of carbachol with each NSAID. All of the drugs were more potent after spinal than after systemic administration. The combinations of NSAIDs and carbachol administered i.p. were supra-additive; however, the i.t. combinations were only additive. Isobolographic analysis of the coadministration of NSAIDs and carbachol and the fact that atropine antagonized the synergistic effect suggest that carbachol may strongly modulate the antinociceptive activity of NSAIDs; thus, central cholinergic modulation would be an additional mechanism for the antinociceptive action of NSAIDs, unrelated to prostaglandin biosynthesis inhibition.

Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. I. Mechanism and evidence of functional significance.

Tenidap is a novel anti-inflammatory and antiarthritic agent that in clinical studies of rheumatoid arthritis patients, displays symptomatic efficacy superior to nonsteroidal anti-inflammatory drugs (NSAIDs) and equivalent to combinations of NSAIDs and second line agents. Clinical and preclinical biochemical studies have demonstrated that tenidap combines cytokine modulation with suppression of prostaglandin biosynthesis. To better understand tenidap's mechanism of action, in vitro studies of intracellular pH (pHi) were conducted. In cells loaded with the pH-sensitive fluorescence dye 2',7'-bis-(2-carboxyethyl)-5-(and -6) carboxyfluorescein, tenidap, but not NSAIDs, caused a rapid and sustained acidification of the cytoplasmic compartment. Tenidap did not act as a proton ionophore, as it did not dissipate the low pH within lysosomes. Mammalian cells regulate pHi through the concerted action of a number of specific transport proteins, including sodium-proton antiporters and chloride-bicarbonate exchangers. Tenidap did not alter pHi via inhibition of the sodium-proton antiporter, but inhibited activity of chloride-bicarbonate exchangers, as did UK5099, a known anion-transport inhibitor that also lowers pHi. This similar activity suggests that the pHi change is coupled to anion transport inhibition. As a result of the pHi change, tenidap affected pH-dependent cellular activities. Tenidap inhibited mannose 6-phosphate receptor-mediated endocytosis, inhibited protein synthesis, and stimulated accumulation of the amino acid leucine. Effects on these cellular processes rapidly reversed when tenidap was removed from the culture medium. Tenidap's in vitro activities were highly dependent on the medium composition; protein content, pH, and bicarbonate concentration all were important factors that influenced activity. These results indicate that tenidap is a potent anion-transport inhibitor and modulator of pHi. Within the appropriate cell or tissue microenvironment, these activities may contribute to tenidap's novel therapeutic profile.