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Evaluation of anti-pyretic and analgesic activity of Emblica officinalis Gaertn.

The present study was designed to investigate the anti-pyretic and analgesic activity of ethanol (EEO) and aqueous (AEO) extracts of Emblica officinalis fruits in several experimental models. A single oral dose of EEO and AEO (500 mg/kg, i.p.) showed significant reduction in brewer's yeast induced hyperthermia in rats. EEO and AEO also elicited pronounced inhibitory effect on acetic acid-induced writhing response in mice in the analgesic test. Both, EEO and AEO did not show any significant analgesic activity in the tail-immersion test. These findings suggest that extracts of Emblica officinalis fruits possessed potent anti-pyretic and analgesic activity. Preliminary phytochemical screening of the extracts showed the presence of alkaloids, tannins, phenolic compounds, carbohydrates and amino acids, which may be responsible for anti-pyretic and analgesic activities.

Analgesics↗

Anti-inflammatory, analgesic and antipyretic effects of methanol extract from Bauhinia racemosa stem bark in animal models.

In this study, the anti-inflammatory, analgesic, and antipyretic effects of 50, 100 and 200 mg/kg body weight of methanol extract obtained from Bauhinia racemosa stem bark, the so-called MEBR, were investigated. The effects of MEBR on the acute and chronic phases of inflammation were studied in carrageenan, dextran and mediators (histamine and serotonin)-induced paw oedema and cotton pellet-induced granuloma, respectively. Analgesic effect of MEBR was evaluated in acetic acid-induced writhing and hotplate tests. Antipyretic activity of MEBR was evaluated by yeast-induced hyperpyrexia in rats. The anti-oedema effect of MEBR was compared with 10 mg/kg of indomethacin orally. In acute phase of inflammation, a maximum inhibition of 44.9, 43.2, 44.8 and 45.9% (P<0.001) was noted at the dose of 200 mg/kg b.w. after 3h of treatment with MEBR in carrageenan, dextran, histamine and serotonin-induced paw oedema, respectively. Administration of MEBR (200 mg/kg b.w.) and indomethacin (10 mg/kg b.w.) significantly (P<0.05) decreased the formation of granuloma tissue induced by cotton pellet method at a rate of 50.4 and 56.2%, respectively. The extract also inhibited peritoneal leukocyte migration in mice. The MEBR also produced significant (P<0.01) analgesic activity in both models. Further, the MEBR potentiated the morphine- and aspirin-induced analgesic in mice. Treatment with MEBR showed a significant (P<0.01) dose-dependent reduction in pyrexia in rats. The results suggest that MEBR possess potent anti-inflammatory, analgesic and antipyretic activity.

Analgesia↗

Effect of nitric oxide synthase inhibition on tolerance to the analgesic action of D-Pen2, D-Pen5 enkephalin and morphine in the mouse.

The effects of NG-nitro-L-arginine (NNA), an inhibitor of nitric oxide synthase (NOS) on the development of tolerance to the analgesic action of D-Pen2, D-Pen5 enkephalin (DPDPE), a delta 1 opioid receptor agonist, and morphine were determined in the mouse. Tolerance to DPDPE was induced in male Swiss-Webster mice by twice daily intracerebroventricular (i.c.v.) injections of the drug (20 micrograms/mouse) for 4 days. NNA was injected intraperitoneally (i.p.) 10 min before each injection of DPDPE. Chronic injections of DPDPE resulted in development of tolerance to its analgesic action. Multiple injections of NNA by itself did not modify the analgesic response to DPDPE. Concurrent injections of NNA did not affect the development of tolerance to the analgesic action of DPDPE. Twice daily injections of morphine (15 mg/kg s.c.) for 4 days resulted in the tolerance to its analgesic action. Concurrent administration of NNA with morphine attenuated the development of tolerance to morphine. It is concluded that NOS inhibition attenuates morphine, but not delta, opioid agonist-induced tolerance in the mouse.

Analgesics↗

[Co-analgesics in the treatment of chronic pain].

Opioids do not yield adequate analgesic effects in at least one-third of all patients suffering from chronic pain. Nonetheless, in contrast to former opinion there is no type of pain that is principally resistant to opioids, which means that the individual patient's response to opioid administration has to be investigated to determine adequate treatment. Opioids fail most frequently in cases of neuropathic, osseous or sympathetically maintained pain. In these cases there is an indication for early use of co-analgesics. The analgesic potency of anticonvulsives and tricyclic antidepressants has been best documented. A differential indication of the large number of possible coanalgesics should be determined with the help of a detailed pain history focussing on the pain quality. Similar to the WHO analgesic ladder used in (tumor) pain therapy, co-analgesic therapy should only be supplemented by invasive therapeutic procedures after various combinations and alternative substances have proven fruitless. Experience shows that this is necessary only for a small number of patients.

Analgesics, Non-Narcotic↗

[Postoperative routine use of physostigmine on vigilance, cardiovascular parameters and need of analgesics].

OBJECTIVE: A central anticholinergic syndrome (CAS) can be related to the majority of anesthetic agents, but is often not recognized as such. Thus, most anesthesiologists seem to miss the occurrence of an anticholinergic syndrome especially when agitation and/or restlessness are the major symptoms. Therefore, the following study was undertaken to test the hypothesis that routine administration of the anticholinergic agent physostigmin is of benefit for patients in regard to vigilance, the cardiovascular system and the need of analgesics easing the time in the post anesthesia care unit (PACU). METHODS: After approval by the local ethics committee and written informed consent, 100 patients undergoing a cholecystectomy or a struma resection, were given either physostigmin (n = 51) or saline 0.9 % (n = 49) in a randomized fashion. The study was conceived to block a possible isoflurane-N2O/O2 (opioid-based plus relaxant) induced central anticholinergic syndrome and to evaluate the effects on the cardiovascular system on vigilance and on postoperative analgesic demand. Following parameters were measured: systolic and diastolic blood pressure, heart rate, respiratory rate, and arterial blood gases. In addition, vigilance was determined and typical anticholinergic symptoms (disorientation, slurred speech, agitation, nausea, emesis, cardiac arrhythmia and muscle shivering) were determined 10, 20, 40 and 60 minutes following the intravenous injection of physostigmin. Also, the need for the postoperative analgesic pethidine was evaluated among the two groups. RESULTS: Except for a significant reduction in the need of analgesics, a reduced diastolic pressure and heart rate and a lower incidence of muscle shivering there was no difference among the two groups. One major side effect following the use of physostigmin was the higher incidence of nausea in the im mediate minutes following injection. This effect may be due to the rapid injection of the anticholinergic compound. Otherwise there were no detrimental effects of physostigmin in patients. CONCLUSION: From the results it can be concluded that routine administration of an anticholinergic agent results in a short term beneficial effect in regard to vigilance, a lesser incidence of muscle shivering and a lesser demand for analgesics. However, because of the low incidence of a classical central anticholinergic syndrome, routine physostigmine is only indicated when agitation is diagnosed.

Adult↗

The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study.

UNLABELLED: Analgesic acetaminophen plasma concentrations are not known. We investigated in a randomized, double-blinded study the pharmacokinetics and analgesic efficacy of small- (AS; 20 mg. kg(-1)) and larger- (AL; 40 mg/kg) dose rectal acetaminophen and compared it with the combination (C) of rectal diclofenac (100 mg) and acetaminophen (20 mg/kg) in 65 women undergoing hysterectomy. Suppositories were administered after the induction of a standardized general anesthesia. Pain (measured by using a 10-cm visual analog scale) and morphine consumption (patient-controlled analgesia) were repeatedly assessed for 24 h. Acetaminophen plasma concentrations were measured by using a fluorescence polarization immunoassay. Antipyretic plasma concentrations (10-20 mg/L) after 40 mg/kg acetaminophen were not associated with improved analgesia or decreased opioid requirements; 20 mg/kg acetaminophen produced subtherapeutic plasma levels (<10 mg/L). Maximal plasma concentrations of 17.2 and 10.4 mg/L (P < 0.01, analysis of variance) were achieved after 4.2 and 3.6 h for the AL and AS groups, respectively. The only difference in clinical outcome was lower visual analog scale scores after acetaminophen/diclofenac (C 2.0 versus AS 3.2 and AL 3.4) 4 h after the induction (P < 0.05, analysis of variance). Acetaminophen pharmacokinetics in adults were similar to those observed in children. Analgesic plasma concentrations are likely to be higher than antipyretic plasma levels, which were only attained after twice the recommended rectal dose was administered. Analgesic plasma concentrations have yet to be determined but may be higher than those associated with antipyresis. IMPLICATIONS: Acetaminophen pharmacokinetics were comparable in adults and children. Plasma concentrations known to reduce fever did not produce better pain relief and were only achieved after twice the conventional dose was administered. Analgesic plasma concentrations have yet to be determined but may be higher than those associated with antipyresis.

Acetaminophen↗

The analgesic effect of gabapentin and mexiletine after breast surgery for cancer.

UNLABELLED: We investigated the analgesic efficacy of mexiletine and gabapentin on acute and chronic pain associated with cancer breast surgery in 75 patients. They were randomized to receive, in a double-blinded manner, mexiletine 600 mg/d, gabapentin 1200 mg/d, or placebo for 10 days. Anesthesia was standardized, and all patients had access to routine postoperative analgesics on demand. The visual analog scale score assessed pain at rest and after movement. Three months later, all patients were interviewed to identify intensity of chronic pain and analgesic requirements. Mexiletine and gabapentin reduced codeine consumed from the second to tenth day by 50% (P = 0.029; P = 0.018 and P = 0.035 for mexiletine versus control and gabapentin versus control comparisons, respectively). Total paracetamol consumption was also reduced during the same time (P = 0.0085; P = 0.007 and P = 0.011 for the mexiletine and gabapentin groups when compared with the control, respectively). Pain at rest and after movement was reduced by both drugs on the third postoperative day. Pain after movement also was reduced by gabapentin between the second and fifth postoperative day. Three months later, the incidence of chronic pain, its intensity, and need for analgesics were not affected by either treatment. However, burning pain was more frequent in the control group (P = 0.033). IMPLICATIONS: Patients undergoing breast surgery for cancer may develop chronic pain. We evaluated the effect of mexiletine and gabapentin on the acute and chronic pain after breast surgery for cancer. Both drugs reduced the postoperative analgesic requirements, and particularly, gabapentin reduced pain after movement. The overall incidence of chronic pain was unaffected except for burning pain.

Acetates↗

Analgesic effects on endogenous melatonin secretion.

Animal welfare concerns have led to increased demands for use of post-operative analgesia in association with experimental surgery. Such treatment is appropriate provided it has no effect on experimental parameters. In order to assess any effects of analgesics on endogenous melatonin production, groups of six ewes were bled at 30 min intervals for the first 4 hr of darkness a) without analgesic treatment and b) immediately after analgesic administration. Analgesics tested were ketoprofen, phenylbutazone (both non-steroidal anti-inflammatory drugs or NSAIDs) and buprenorphine (an opioid). Plasma melatonin was measured by radioimmunoassay and 4 hr secretion profiles computed for each animal. Ketoprofen and buprenorphine treatment reduced mean four hour melatonin secretion profiles by 50.6% (from 1,347.3 to 665.1 pg/ml.hr) and 38.6% (from 287.8 to 171.3 pg/ml.hr), respectively. Only in the case of phenylbutazone was the response not statistically significant; hence this drug has been selected as a post-operative analgesic for future experimental studies involving measurement of melatonin levels.

Analgesics↗

The analgesic efficacy of valdecoxib vs. oxycodone/acetaminophen after oral surgery.

BACKGROUND: The authors conducted two studies to compare the analgesic efficacy and safety of the cyclooxygenase, or COX, -2-specific inhibitor, valdecoxib, with oxycodone/ acetaminophen in patients who have undergone oral surgery. METHODS: In total, 205 eligible subjects in Study A and 201 in Study B were randomized to receive a single oral dose of valdecoxib (20 or 40 milligrams), a combination of oxycodone 10 mg/acetaminophen 1,000 mg or placebo. Eligible subjects experienced moderate-to-severe pain within six hours of surgery during which two or more impacted third molars were extracted. Analgesic efficacy was assessed over 24 hours or until the patient required rescue analgesia. RESULTS: In both studies, subjects receiving either dose of valdecoxib experienced a rapid onset of analgesia and (among those who received valdecoxib 40 mg) a level of pain relief comparable with that of those who received oxycodone/ acetaminophen. Both valdecoxib doses had a significantly longer duration of analgesic effect than did oxycodone/acetaminophen. Pooled safety data demonstrated that each valdecoxib dose had a tolerability profile superior to that of oxycodone/ acetaminophen and similar to that of placebo. CONCLUSIONS: Orally administered valdecoxib is as rapidly acting and effective as oxycodone/acetaminophen, and it has a superior duration of analgesic effect in patients after oral surgery. Valdecoxib has a tolerability profile superior to that of oxycodone/acetaminophen. CLINICAL IMPLICATIONS: The current standard of care for alleviating acute pain after oral surgery has rested largely on conventional nonsteroidal anti-inflammatory drugs or opioid/analgesic combination products. The studies reported here suggest that the COX-2-specific inhibitor valdecoxib offers an efficacious and safe alternative to other analgesics used to treat pain after oral surgery.

Acetaminophen↗

Adjuvant analgesics in cancer pain management.

Adjuvant analgesics are defined as drugs with a primary indication other than pain that have analgesic properties in some painful conditions. The group includes numerous drugs in diverse classes. Although the widespread use of these drugs as first-line agents in chronic nonmalignant pain syndromes suggests that the term "adjuvant" is a misnomer, they usually are combined with a less-than-satisfactory opioid regimen when administered for cancer pain. Some adjuvant analgesics are useful in several painful conditions and are described as multipurpose adjuvant analgesics (antidepressants, corticosteroids, alpha(2)-adrenergic agonists, neuroleptics), whereas others are specific for neuropathic pain (anticonvulsants, local anesthetics, N-methyl-D-aspartate receptor antagonists), bone pain (calcitonin, bisphosphonates, radiopharmaceuticals), musculoskeletal pain (muscle relaxants), or pain from bowel obstruction (octreotide, anticholinergics). This article reviews the evidence supporting the use of each class of adjuvant analgesic for the treatment of pain in cancer patients and provides a comprehensive outline of dosing recommendations, side effects, and drug interactions.

Adrenal Cortex Hormones↗

Transition between anesthesia and post-operative analgesia: relevance of intra-operative administration of analgesics.

The rapid awakening without residual analgesic effect seen with the new "fast-in-fast-out" anesthetic agents forces us to anticipate post-operative pain management. More then ever, "balanced analgesia" appears the key for successful transition between anesthesia and post-operative analgesia. This review focuses on practical aspects seeking to answer the following questions: which analgesics should be used?; how should they be given?; at what stage of the anesthetic time should they be injected? In the absence of a loco-regional technique, analgesics must be given before the end of surgery to obtain a quiet awakening. The transition in this delicate period may be facilitated by the intra-operative use of various adjuvant therapies such as ketamine, lidocaine infusion, clonidine, and magnesium, that reduce the needs for opioid and/or post-operative pain severity. All non-opioid analgesics (propacetamol, NSAIDs, tramadol) must be given according to their pharmacokinetic characteristics, indications and contraindications to ensure the required analgesic effect is effective at the time of awakening. If tramadol is not used, an initial dose of a long-acting opioid should be given 20-30 minutes before the end of surgery. Insufficient analgesia must be corrected by titrating an opioid intravenously before allowing the patient to control his/her analgesia using a PCA pump.

Analgesics↗

[Use of analgesics with peripheral action in the system of complex protection of the patient from operative trauma].

Obtained for many years experience of perioperative using of analgesics with peripheral effect is summarized. The special scientific analysis was carried out in 274 patients who got different analgesics with peripheral action (aspisol, baralgin, ketoprofen, ketorolak, contrikal) at different stages of preoperative period in combination with opioid. The control group included 30 patients who got monoanalgesia by promedol after abdominal operations. The dynamics of pain, hemodynamics, respiration, gas-exchange, blood coagulation and rheology indices as well as side effects of analgesics were estimated. The best results have been obtained in cases with preventive therapy by non-steroid anti-inflammatory drug 1 hour before beginning of operation and subsequent therapy continuation after operation. Under such conditions complete analgesia after operation with moderate traumaticity is achieved in combination with low dose of small opioid (tramal) in daily dose of 235 mg. The introducing of non-steroid anti-inflammatory drugs was not followed by any hemorrhagic complication, and as was evident from electrocoalugraphic data improved blood rheology. After severe traumatic abdominal or thoracal operations non-steroid anti-inflammatory drugs are used in combination with other potent analgesic with peripheral action--cortical and opioid buprenofine in minimal dose of 0.35 mg/day with good analgesic effect. To prevent the central sensitization during general anesthesia ketamine in microdose 0.5-1.0 mg/kg*hour is always used. The conclusion is made on the important role of multimodal preventive and continuous perioperative antinociceptive protection.

Analgesia↗

The new analgesic combination tramadol/acetaminophen.

BACKGROUND: Combinations of analgesic drugs provide the opportunity for better efficacy with less overall morbidity than provided by single analgesic agents. This article discusses the rationale, efficacy and safety for a novel analgesic combination: tramadol and acetaminophen (paracetamol). METHODS: Data supporting the rationale of combining tramadol and acetaminophen to provide pain relief will be reviewed in addition to clinical data demonstrating the efficacy and safety of this combination in acute and chronic pain states. RESULTS: Tramadol and acetaminophen are a rational combination product in that their mechanisms of action do not overlap and that in preclinical studies this combination acts synergistically. Also, this combination would be expected to provide more rapid pain relief than tramadol alone, and more persistent pain relief than acetaminophen alone. Moreover, each compound is broken down along separate metabolic pathways. Acute dental pain studies showed that pain relief and improvements in pain intensity associated with tramadol 75 mg plus acetaminophen 650 mg are superior to placebo, or tramadol or acetaminophen alone. This combination provided a rapid onset of action, identical to that achieved with acetaminophen alone, but the pain relief was also sustained, as for tramadol alone. Tramadol/acetaminophen also had the same adverse event profile as tramadol monotherapy. A chronic low back/osteoarthritic pain study showed that the drug combination can also be used similarly to codeine/acetaminophen combinations in treating benign chronic pain. The safety profile of the tramadol/ acetaminophen combination is at least as favourable as that of codeine/acetaminophen, and is well tolerated with long-term use. CONCLUSIONS: Tramadol/acetaminophen combination is a new preparation that is effective in acute or chronic moderate-to-moderately severe pain. It benefits from the complementary actions of the constituent analgesics, having the rapid onset of acetaminophen and the sustained effect of tramadol. The analgesic efficacy of this combination is comparable to that of positive controls, and its adverse event profile is in line with that of its single components.

Acetaminophen↗

Postoperative use of analgesics in dogs and cats by Canadian veterinarians.

Four hundred and seventeen Canadian veterinarians were surveyed to determine their postoperative use of analgesics in dogs and cats following 6 surgical procedures, and to determine their opinions toward pain perception and perceived complications associated with the postoperative use of potent opioid analgesics. Three hundred and seventeen (76%) returned the questionnaire. The percentage of animals receiving analgesics postoperatively ranged from 84% of dogs and 70% of cats following orthopedic surgery to 10% of dogs and 9% of cats following castration. In general, with the exception of orthopedic surgery, roughly equal percentages of dogs and cats received postoperative analgesics. Opioids were used almost exclusively to provide postoperative analgesia, with butorphanol the most commonly administered drug to both dogs and cats. Analgesics were usually administered either once or twice postoperatively. With regard to the administration of potent opioid agonists, the 3 major concerns included respiratory depression, bradycardia, and sedation in dogs, and excitement, respiratory depression, and bradycardia in cats. Seventy-seven percent of veterinarians considered their knowledge of issues related to the recognition and control of postoperative pain to be inadequate. Experience in practice is currently the major source of knowledge, with undergraduate veterinary school and research articles in journals ranked as the least important sources. Lectures or seminars delivered at the regional level were the preferred format for continuing education.

Analgesics↗

Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat.

Despite its frequent clinical use in analgesic agents, caffeine has not been accepted unequivocally as an analgesic adjuvant. To evaluate this activity of caffeine, we used new study methods in a randomized controlled trial on patients with acute sore throat due to tonsillopharyngitis. Patients were randomly assigned to receive a single dose of one of three treatments: 800 mg of aspirin with 64 mg of caffeine (n = 70), 800 mg of aspirin (n = 68), or placebo (n = 69). Under double-blind conditions, during a 2-hour evaluation period, patients used different rating scales to assess pain intensity, change in pain, relief, and two qualities of throat pain, how swollen the throat felt, and difficulty swallowing. Aspirin with caffeine and aspirin alone were significantly more effective than placebo for all efficacy measurements from 30 minutes through 2 hours and overall. The aspirin-caffeine combination also showed evidence of activity at 15 minutes on the relief scale. Aspirin with caffeine was more effective than aspirin alone after 30 minutes and over the entire study period. For patients with fever, both active treatments were equally effective antipyretic agents. We conclude, therefore, that 800 mg of aspirin, given alone or with 64 mg of caffeine, is an effective analgesic and antipyretic agent. Because the aspirin-caffeine combination is significantly more effective than aspirin alone as an analgesic, we also conclude that 64 mg of caffeine is an analgesic adjuvant.

Adult↗

Analgesic efficacy and safety of (R)- ketoprofen in postoperative dental pain.

This double-blind, randomized, parallel-group study compared the analgesic efficacy and safety of single doses of (R)- ketoprofen 25 mg and 100 mg to that of acetaminophen 1,000 mg and placebo in 177 patients experiencing moderate to severe pain after surgical removal of their impacted third molars. Both (R)- ketoprofen 100 mg and acetaminophen 1,000 mg were significantly (P < 0.05) more efficacious than placebo for all summary analgesic measures. Other than a more rapid analgesic onset (45 minutes versus 60 minutes) for acetaminophen 1,000 mg, (R)- ketoprofen 100 mg and acetaminophen 1,000 mg were statistically equivalent to each other. The 25 mg dose of (R)- ketoprofen appeared to approach the analgesic threshold dose, being numerically but not statistically superior to placebo for all summary measures. There were no serious adverse events observed in this study, with the overall incidence of side effects being somewhat less in the (R)- ketoprofen groups than in the acetaminophen 1,000 mg group. (R)- Ketoprofen possesses analgesic activity and an acceptable side-effect profile in the oral surgery pain model.

Acetaminophen↗

Mutagenic and analgesic activities of aniline derivatives.

Phenacetin (1), acetaminophen (2), acetanilide (3), 4-aminophenol (4), and aniline (5) were tested in S.J.L. Swiss mice for their mutagenic and analgesic activities. The S-analogues of 1 and 2, 4-mercaptoacetanilide (6) and 4-ethylthioacetanilide (7), respectively, were synthesized and tested in the same way to define if both activities could be separated by molecular modification. All the compounds tested exhibited analgesic activity with ED50 values ranging from 12.6 to 158.5 mg/kg. The compounds could be arranged in a decreasing order of analgesic activity as follows: 3 greater than 4 congruent to 5 congruent to 6 greater than 1 congruent to 7 greater than 2. All the compounds, except 6, were positive mutagens in the micronucleus test (statistically significant). The order of relative mutagenic potencies was 1 congruent to 7 greater than 4 greater than 2 congruent to 3 congruent to 5. A narrow dose-response curve relationship was found for 5 and its metabolite 4, the relative mutagenic potencies of which suggest ring hydroxylation as the major pathway of biotoxification. No parallelism was found between analgesic and mutagenic activities, so they could be separated by pharmacomodulation: 6 was more effective as an analgesic in the acetic acid test than 2, and no mutagenic activity was found at the doses assayed.

Acetates↗

Analgesic studies on total alkaloids and alcohol extracts of Eclipta alba (Linn.) Hassk.

A variety of analgesics are used for the treatment of acute and chronic pain in different disease states. A narcotic or a non-narcotic analgesic that does not cause respiratory depression and addiction is needed. In Ayurveda a large number of indigenous drugs have been mentioned possessing analgesic properties (e.g. Guggul, Erand, Rasna, Bhringaraj, Methika, Palandu and Prasikayavani). The present experimental research work was undertaken to determine the analgesic activity of the total ethanol extract of Eclipta alba, and also the isolated alkaloids of Eclipta alba in albino mice by using standard experimental models such as the tail clip method, the tail flick method and the acetic acid induced writhing response. The results from this study show that both the ethanol extract as well as the total alkaloids produce good analgesic activity in all the different models of analgesia used. The total alkaloidal fraction was the most efficacious in all models tested.

Acetic Acid↗