High Analgesic Potency Research Articles

Immune Mechanisms in Pain Control

Immune Mechanisms in Pain Control

AGGRESSIVE PHARMACOLOGIC TREATMENT OF PAIN

In this article, the author outlines the pharmacology of nociception and discusses the two major classes of drugs used for pain control: opioids and nonopioid analgesics. In order to provide satisfactory pain relief and prevent the possible sequelae of untreated pain, physicians must possess both knowledge and expertise in the use of opioid and nonopioid analgesics. Opioid analgesics have been underused in the management of pain. Opioids have a higher analgesic potency and wider range of indications than any of the other currently available medications for pain control. The second class of drugs, the nonopioid analgesics and adjuvants, has recently expanded to include new and potentially beneficial medications. This article furthers the understanding on how to use analgesics for a prompt, safe, and effective pharmacologic treatment of acute and chronic pain.

Synthesis, X-ray analysis and spectroscopic characterization of the hemiaminal cyclization product from 2,4-dipyridine substituted 3,7-diazabicyclo[3.3.1]nonanone 1,5-diesters

The 2,4-dipyridine substituted 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one 1,5-diester, HZ2, is characterized by a high analgesic potency. The attempt to form ammonium salts of HZ2 or to N-demethylate position 7 resulted in an unexpected hemiaminal cyclization product 1. The structure was elucidated by an X-ray analysis, the 1H- and 13C-NMR spectra could be fully assigned by means of H,H-COSY, Grad-HSQC-EA and ACCORD-HMBC experiments. The MS spectra of 1 exhibit a ring opening. Interestingly, ESI-MS/MS experiments of HZ2 in aqueous solution showed the formation of a hydrated product. The fragmentation pathways of HZ2 and the hydrated product are rather different indicating the formation of a carboxylate.

Synthesis and biological activity of branched enkephalin analogues

The synthesis and biological activity of a new type of enkephalin analogs are reported. A series of branched pentapeptides of the enkephalin sequence with replacement of 2-glycine by D-ornithine and branching of the peptide chain in position 2 by attachment of proline, leucine, asparagine or methionine residues to the δ-amino group of D-ornithine were synthesized by classical solution methodology. Analgesic activity of the new analogs was assayed by the ‘tail pinch’ method following intracisternal and intravenous administrations to mice. They showed higher analgesic potency and longer duration of action as compared to linear and cyclic pentapeptides with the same amino acid composition. The activity determined in the GPI and MVD bioassays, and in a binding assay, revealed the preference of the branched analogs for the μ-type of opioid receptor over the δ-type. These results raise the possibility to synthesize enkephalin analogs with high analgesic potency and opiate receptor selectivity by varying the chemical character and length of the side chain in the 2-position.

Preclinical and clinical development of dexketoprofen.

Dexketoprofen trometamol is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen. Racemic ketoprofen is used as an analgesic and an anti-inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis. This effect is due to the S(+)-enantiomer (dexketoprofen), while the R(-)-enantiomer is devoid of such activity. The pharmacokinetic profile of ketoprofen and its enantiomers was assessed in several animals species and in human volunteers. In humans, the relative bioavailability of oral dexketoprofen trometamol (12.5 and 25 mg, respectively) is similar to that of oral racemic ketoprofen (25 and 50 mg, respectively), as measured in all cases by the area under the concentration-time curve values for S(+)-ketoprofen. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (tmax) of between 0.25 and 0.75 hours, whereas the tmax for the S-enantiomer after the racemic drug, administered as tablets or capsules prepared with the free acid, is between 0.5 and 3 hours. Peak plasma concentrations of 1.4 and 3.1 mg/L are reached after administration of dexketoprofen trometamol 12.5 and 25 mg, respectively. From 70 to 80% of the administered dose is recovered in the urine during the first 12 hours, mainly as the acyl-glucuronoconjugated parent drug. No R(-)-ketoprofen is found in the urine after administration of dexketoprofen [S(+)-ketoprofen], confirming the absence of bioinversion of the S(+)-enantiomer in humans. in animal studies, the anti-inflammatory potency of dexketoprofen was always equivalent to that demonstrated by twice the dose of ketoprofen. Similarly, animal studies showed a high analgesic potency for dexketoprofen trometamol. The R(-)-enantiomer demonstrated a much lower potency, its analgesic action being apparent only in conditions where the metabolic bioinversion to the S(+)-enantiomer was significant. The gastric ulcerogenic effect of dexketoprofen at various oral doses (1.5 to 6 mg/kg) in the rat do not differ from those of the corresponding double doses (3 to 12 mg/kg) of racemic ketoprofen. Repeated (5-day) oral administration of dexketoprofen as the trometamol salt causes less gastric ulceration than was observed after the acid form of both dexketoprofen and the racemate. In addition, single dose dexketoprofen as the free acid at 10 to 20 mg/kg does not show a significant intestinal ulcerogenic effect in rats, while racemic ketoprofen 20 or 40 mg/kg is clearly ulcerogenic to the small intestine. The analgesic efficacy of oral dexketoprofen trometamol 10 to 20 mg is superior to that of placebo and similar to that of ibuprofen 400 mg in patients with moderate to serve pain after third molar extraction. The time to onset of pain relief appeared to be shorter in patients treated with dexketoprofen trometamol than in those treated with ibuprofen 400 mg. Dexketoprofen trometamol was well tolerated, with a reported incidence of adverse events similar to that of placebo.

Analgesic profile of the sodium salt of pemedolac

AbstractPemedolac Na, 1‐ethyl‐1,3,4,9‐tetrahydro‐4‐(phenylmethyl)‐pyrano [3,4‐b] indole‐1‐acetic acid sodium salt, exhibited equipotent analgesic effects after oral, iv, and im administration, suggesting that it is well absorbed. In mouse writhing models, the ED50 values ranged from 0.3 mg (0.81 μmol)/kg (vs. acetylcholine) to 4.3 mg (11.6 μmol)/kg (vs. paraphenylbenzoquinone [PBQ]). In the rat Randall‐Selitto model, the ED50 o the compound was approximately 0.001 mg (2.7 nmol)/kg, with a flat dose response curve. The peak effects lasted for 7–9 h, 10–18 h, and 5 h following oral, im, and iv injections, respectively. Intracerebroventricular (i.c.v.) injections of pemedolac Na inhibited the PBQ‐induced writing in mice with an ED50 of 43.5 μg (0.12 μmol)/mouse, and this effect was not antagonized by naloxone. It was inactive in the hot plate and tail flick tests, demonstrating that pemedolac Na does not act via an opiate mechanism. These results indicate that pemedolac Na is a viable parenteral and oral analgesic, typified by high analgesic potency, a rapid onset and long duration of action, and an extremely wide safety index. © Wiley‐Liss, Inc.

Linear and cyclic β-casomorphin analogues with high analgesic activity

We investigated the antinociceptive efficacy of casomorphin (CM) derivatives using the vocalization test. Male Wistar rats received chronic microcannulae into the right lateral ventricle. One week later we examined the analgesic effect of CM derivatives 10, 30, 60, and 90 min after intraventricular injection (5 μl). The analgesic effect was calculated as the individual percent increase in the pain threshold and was compared to controls (saline treatment). The substitution of d-lysine and d-ornithine in position 2 in connection with a cyclization through ring closure of the 2 position side chain amino group to the C-terminal glycine-COOH group resulted in high analgesic potency. The substitution of d-Pro 4 was without any effect in the ineffective linear derivatives and decreased the effectiveness in the highly effective cyclic derivatives. The cyclic [ d-Orn 2]CM-5 and the cyclic [ d-Lys 2]CM-5 are the CM derivatives with the highest antinociceptive activity. The cyclic [ d-Orn 2]CM-5 is greater than 1000 times more effective than morphine. We conclude, on the basis of studies of receptor binding and in vitro investigations, that μ receptor activity alone is not responsible for the analgesic activity. The δ receptor and possibly also the κ receptor could modulate the nociceptive effectiveness.

Opioids and behavior: genetic aspects.

Three animal models, based on genetic differences in endogenous opioid peptides and opioid receptors, are described. Obese mice and rats, whose pituitary opioid content is elevated, may be used to investigate eating disorders. Recombinant inbred strains of mice, which differ in brain opioid receptors and analgesic responsiveness, can be used for study of opioid- and nonopioid-mediated mechanisms of pain inhibition. Individual reactivity to opioids can be examined in C57BL/6 and DBA/2 inbred strains of mice. A model that combines a variety of opioid effects is offered and suggests the existence of a genetically determined dissociation of opioid effects on locomotor activity and pain inhibition. In addition, stimulatory locomotor responses in the C57BL/6 reaction type are linked to a high risk of drug addiction and facilitatory effects on adaptive processes, while high analgesic potency in the DBA/2 reaction type is accompanied by a low proneness to drug abuse and amnesic properties of opioids.

Derivatives of β-casomorphins with high analgesic potency

β-Casomorphin (5) Tyr-Pro-Phe-Pro-Gly, a partial sequence of bovine β-casein with moderate opioid properties and μ-receptor affinity, was modified by substituting for the natural L-amino acids their D-analogs, and D-pipecolic acid, as well as by amidation of the C-terminal. Substitution of D-Pro or D-pipecolic acid for L-Pro 4 considerably increased the analgesic action and the potency on guinea-pig ileum of β-casomorphin (5) as well as of casomorphin [4] amide. The resulting D-Pro 4 analogs Deprolorphin and Deproceptin which showed high analgesic potency after both intracerebroventricular and intravenous administrations. Also, the substitution of D-Phe for L-Phe 3 enhanced, even though to a lesser degree, the antinociceptive action. Both naltrexone and naloxone completely blocked the effects in vivo and in vitro. The substitution of D-Pro for L-Pro 2 abolished the opioid-like actions, while substituting D-pipecolic acid for L-Pro 2 resulted in an increased analgesic effect of remarkably long duration. The correlation of analgesic action with the effects on isolated organs separates the L-Pro 4-substituted derivatives and D-Phe 3-CM(5) from the other modified casomorphins and morphine, indicating that the analgesic potency of the former was about ten times that of the latter group in the case of identical GPI-potency. This may involve different subpopulations of opiate μ-receptors.

Analgesic activity of lipotropin C fragment depends on carboxyl terminal tetrapeptide

A SERIES of peptides with morphine-like activity has been identified in extracts of pituitary1–3 and brain4–7. With the exception of Leu-enkephalin, all those characterised represent some fraction of the 31-residue C fragment—a specific activation product of lipotropin1,8. Several attempts have been made to define the receptor requirements of opiate peptides9,10 and to make potent and stable agonists5,11,12, but essentially all the studies have been based on the easily synthesised NH2-terminal pentapeptide of C fragment, Met-enkephalin. Unlike the enkephalins, C fragment has a high potency in its central actions13–16, in vivo and in vitro, and it is relatively stable to brain peptidases17–19. C fragment is the only naturally occurring peptide to possess strong analgesic properties and have a long lasting action20. It is clear that specific regions of the molecular structure, not present in γ and α endrophin or Met-enkephalin, have a role in the expression of its central activity. We present here evidence that the COOH-terminal tetrapeptide of C fragment, Lys-Lys-Gly-Gln, is responsible for the unique affinity of C fragment for brain opiate receptors and that the presence of all four residues is essential for the high analgesic potency.

Stereoisomeric 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphans, strong analgesics with non-morphine-like action profiles.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.

STUDIES ON ANALGESIC AGENTS: (PART VI) ANALGESIC EFFECT OF l-BUTYRYL-4-CINNAMYLPIPERAZINE HYDROCHLORIDE

For many years there has been an extensive search for agents as effective as morphine in the relief of pain yet free from the hazard of addiction. Until recently it had appeared that this search would be fruitless. Authors have investigated acetylpiperazine derivatives, and found that 1, 4-bis (2-methoxy-4-propylphenoxyacetyl) piperazine had an analgesic activity without narcotic action (1). This drug, however, does not have good solubility in water and cannot be absorbed from the intestine easily. Thus, this drug appeared to have less analgesic potency when administered orally. In order to overcome this disadvantage, we have carried out further investigations on many other piperazines and found that 1-butyryl-4-cinnamylpiperazine hydrochloride (hereafter referred to as AP-237) had high analgesic potency (2) and good solubility in water. This paper describes the results of more detailed studies on the analgesic effects of AP-237.

Studies of analgesic drugs. VI. Comparative respiratory depressant activity of phenazocine and morphine.

Phenazocine, the first benzomorphan compound to be used clinically, has been shown to be a potent analgesic in man. Early studies with this drug suggested that it possessed high analgesic potency, few respiratory or circulatory side effects, and low addiction liability In this study, the relative respiratory depressant activity of equivalent analgesic doses of phenazocine and morphine were determined in normal adult males. Although there was significantly less respiratory depression I hour after phenazocine than after morphine, this difference was small and probably not of clinical significance. Respiratory depression persisted 3 hours after phenazocine, whereas morphine depression was waning at this time. On the basis of respiratory effects, peak action of phenazocine occurred between 30 and 90 minutes after intramuscular administration, and it persisted longer than morphine.

Alphaprodine (nisentil) hydrochloride in anesthesia; its use, with or without antagonists, for supplementation or as sole agent.

• Alphaprodine (Nisentil) was used as the narcotic analgesic in 209 patients undergoing a variety of major and minor surgical operations. It was given intravenously in amounts ranging from single doses of 30 mg. to multiple doses totaling 1,620 mg. These doses generally exceeded by for what would ordinarily be considered safe; their use was made possible by the simultaneous administration of levallorphan (148 cases) or nalorphine (49 cases), which prevented respiratory depression but did not interfere with the pain-relieving effect. The analgesia so attained was satisfactory, and supplementation with other anesthetics, whether local or general, was in many cases unnecessary. Alphaprodine was thus found to have a high analgesic potency that becomes especially manifest if levallorphan is used at the same time to offset the respiratory depression caused by it. The combination should be used more widely either as the sole anesthetic agent or to supplement others.

Observations of 3-hydroxy-n-methylmorphinan hydrobromide (Dromoran) on fetal respiratory movements of the rabbit.

Discussion and SummaryDromoran® passes without difficulty across the placental barrier and produces a decrease in the rate of respiratory movements of the fetuses. This passage across the placental barrier might be expected in view of the general principle stated by Needham(8) that the placental barrier is freely passed by practically all substances of low molecular weight. Thus in obstetrical analgesia one can assume that the agent will pass the placental barrier and the best analgesic will be one which will have high analgesic potency in the mother and a minimal effect on fetal respiration activity. The final evaluation of an analgesic must therefore be made under clinical conditions where the analgesic property can be evaluated in the patient. The doses of Dromoran® used in these experiments were much higher than would be used for human patients and there is no doubt but what satisfactory analgesia in humans can be obtained with lower doses. The question of whether these doses depress the respiratory f...