Maree T. Smith

Morphine-3-glucuronide - a potent antagonist of morphine analgesia

Abstract In this study, morphine-3-glucuronide (M3G), the major plasma and urinary metabolite of morphine, was shown to be a potent antagonist of morphine analgesia when administered to rats by the intra-cerebroventricular (i.c.v.) route. The antagonism of morphine analgesia was observed irrespective of whether i.c.v. M3G (2.5 or 3.0μg) was administered 15 mins prior to or 15 mins after i.c.v. morphine (20μg). When M3G (10mg) was administered intraperitoneally (i.p.) to rats 30–40 mins prior to morphine (1.5mg i.p.), the analgesic response was significantly reduced compared to administration of morphine (1.5mg i.p.) alone. It was further demonstrated that i.c.v. M3G (2.0μg) antagonized the analgesic effects of subsequently administered i.c.v. morphine-6-glucuronide (0.25μg).

The pharmacokinetics of midazolam in man

SummaryMidazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1–2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25–0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37±0.45 h) did not differe significantly (‘t’=2.04, df=10,p>0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74±0.45 h). The terminal half-life, (t1/2), of midazolam in plasma was 1.77±0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383±0.094 l·kg−1·h−1. The first pass effect, F, determined experimentally (0.36±0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%–0.028%).

Neuroexcitatory effects of morphine and hydromorphone: Evidence implicating the 3-glucuronide metabolites

1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain.

The intrinsic antinociceptive effects of oxycodone appear to be κ-opioid receptor mediated

&NA; Our previous studies in the Sprague–Dawley rat showed that the intrinsic antinociceptive effects of oxycodone are naloxone reversible in a manner analogous to morphine but that in contrast to morphine, oxycodones antinociceptive effects have a rapid onset of maximum effect (≈5–7 min compared to 30–45 min for morphine), comprise one antinociceptive phase (compared to two phases) and are of relatively short duration (≈90 min compared to ≈180 min). In the present study, administration of a range of selective opioid receptor antagonists has shown that the intrinsic antinociceptive effects of oxycodone (171 nmol) are not attenuated by i.c.v. administration of (i) naloxonazine, a &mgr;1‐selective opioid receptor antagonist, or (ii) naltrindole, a &dgr;‐selective opioid receptor antagonist, in doses that completely attenuated the intrinsic antinociceptive effects of equipotent doses of the respective &mgr;‐ and &dgr;‐opioid agonists, morphine and enkephalin‐[d‐Pen2,5] (DPDPE). Although &bgr;‐funaltrexamine (&bgr;‐FNA) attenuated the antinociceptive effects of oxycodone (171 nmol i.c.v.), it also attenuated the antinociceptive effects of morphine and bremazocine (&kgr;‐opioid agonist) indicative of non‐selective antagonism. Importantly, the antinociceptive effects of oxycodone (171 nmol i.c.v.) were markedly attenuated by the prior i.c.v. administration of the selective &kgr;‐opioid receptor antagonist, norbinaltorphimine (nor‐BNI), in a dose (0.3 nmol) that did not attenuate the antinociceptive effects of an equipotent dose of i.c.v. morphine (78 nmol). Taken together, these data strongly suggest that the intrinsic antinociceptive effects of oxycodone are mediated by &kgr;‐opioid receptors, in contrast to morphine which interacts primarily with &mgr;‐opioid receptors.

The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices.

&NA; N‐type calcium channels modulate the release of key pro‐nociceptive neurotransmitters such as glutamate and substance P (SP) in the central nervous system. Considerable research interest has focused on the therapeutic potential of the peptidic &ohgr;‐conopeptides, GVIA and MVIIA as novel analgesic agents, due to their potent inhibition of N‐type calcium channels. Recently, the novel peptidic N‐type calcium channel blocker, AM336, was isolated from the venom of the cone snail, Conus catus. Thus, the aims of this study were to (i) document the antinociceptive effects of AM336 (also known as CVID) relative to MVIIA following intrathecal (i.t.) bolus dosing in rats with adjuvant‐induced chronic inflammatory pain of the right hindpaw and to (ii) quantify the inhibitory effects of AM336 relative to MVIIA on K+‐evoked SP release from slices of rat spinal cord. Both AM336 and MVIIA inhibited the K+‐evoked release of the pro‐nociceptive neurotransmitter, SP, from rat spinal cord slices in a concentration‐dependent manner (EC50 values=21.1 and 62.9 nM, respectively), consistent with the antinociceptive actions of &ohgr;‐conopeptides. Following acute i.t. dosing, AM336 evoked dose‐dependent antinociception (ED50≈0.110 nmol) but the doses required to produce side‐effects were an order of magnitude larger than the doses required to produce antinociception. For i.t. doses of MVIIA≤0.07 nmol, dose‐dependent antinociception was also produced (ED50≈0.016 nmol). Unexpectedly, however, i.t. doses of MVIIA>0.07 nmol, produced a dose‐dependent decrease in antinociception but the incidence and severity of the side‐effects continued to increase for all doses of MVIIA investigated, suggesting that dose‐titration with MVIIA in the clinical setting, may be difficult.

Oxycodone and morphine have distinctly different pharmacological profiles: Radioligand binding and behavioural studies in two rat models of neuropathic pain

Abstract Previously, we reported that oxycodone is a putative κ‐opioid agonist based on studies where intracerebroventricular (i.c.v.) pre‐treatment of rats with the κ‐selective opioid antagonist, nor‐binaltorphimine (nor‐BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (μ‐selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor‐BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)‐diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post‐STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an ∼3‐ to 4‐fold decrease in potency. In rat brain membranes irreversibly depleted of μ‐ and δ‐opioid binding sites, oxycodone displaced [3H]bremazocine (κ2‐selective in depleted membranes) binding with relatively high affinity whereas the selective μ‐ and δ‐opioid ligands, CTOP (d‐Phe‐Cys‐Tyr‐d‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2) and DPDPE ([d‐Pen2,5]‐enkephalin), respectively, did not. In depleted brain membranes, the κ2b‐ligand, leu‐enkephalin, prevented oxycodone’s displacement of high‐affinity [3H]bremazocine binding, suggesting the notion that oxycodone is a κ2b‐opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a κ2b‐opioid agonist with a relatively low affinity for μ‐opioid receptors.

Single‐dose and steady‐state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer

The single‐dose and steady‐state pharmacokinetics and pharmacodynamics of oxycodone have been determined in patients with moderate to severe cancer pain. The mean ± SD elimination half‐life after single‐dose administration of intravenous (4.6 mg to 9.1 mg) and oral (9.1 mg) oxycodone was 3.01 ± 1.37 hours and 3.51 ± 1.43 hours, respectively. After intravenous administration, the mean ± SD volume of distribution was 211.9 ± 186.6 L, and the mean ± SD total plasma clearance was 48.6 ± 26.5 L/hr. The mean absolute oral bioavailability of oxycodone was 87%, and the mean ± SD volume of distribution after oral administration was 249.1 ± 204.3 L. When administered orally as 10 mg oxycodone hydrochloride every 4 hours, there was no accumulation of oxycodone at steady state and the mean ± SD steady‐state concentration was 34.6 ± 10.3 μg/L. Intravenous oxycodone produced a faster onset of pain relief than oxycodone tablets, but the duration of analgesia was approximately the same (4 hours). However, the incidence of side effects and their severity were significantly higher (p < 0.05) for intravenous oxycodone than for oxycodone tablets. The marked interindividual variation observed in the pharmacokinetics and pharmacodynamics of oxycodone in this study supports the need for individualized dosing regimens.

PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models

Background:PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models.Methods:The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens.Results:PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours.Conclusion:PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials.

An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy.

Neuropathic pain is a persistent pain condition that develops secondary to nerve injury. The two most common types of peripheral neuropathic pain are post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN). Amitriptyline, nortriptyline, desipramine and imipramine are TCAs that have been shown to be effective for the symptomatic relief of PHN and PDN. Serotonin noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine have been shown to be very promising for the treatment of PDN with fewer adverse effects than TCAs. Selective serotonin reuptake inhibitors (SSRIs) were shown in a number of studies to have some efficacy in relieving PDN-related pain, yet other studies of the SSRIs have demonstrated conflicting outcomes.Most of the older antiepileptic studies were performed in patients with PDN; consequently, little is known about the efficacy of these drugs in patients with PHN. Carbamazepine, phenytoin and valproic acid were shown to be effective in ameliorating PDN-related pain. Other antiepileptic agents, including lamotrigine, oxcarbazepine and topiramate, have demonstrated some beneficial effects for the treatment of PDN, although they were also found to be ineffective in some PDN studies. α2δ Ligands such as gabapentin and pregabalin have been proven to be effective for the treatment of PHN and PDN in a number of large placebo-controlled trials. These drugs are useful not only in relieving pain but also in improving quality of life.Although the use of opioids for the treatment of neuropathic pain is controversial, a number of studies support the efficacy and safety of opioids in the treatment of neuropathic pain. Of these, oxycodone and tramadol have been shown to be superior to placebo for the treatment of PHN and PDN. A number of small studies have shown that dextromethorphan was effective in patients with PDN but not in patients with PHN.Topical agents such as lidocaine 5% patches and topical capsaicin are useful in ameliorating pain in patients with PHN but these agents are unsatisfactory for use as a sole agent.Although a number of drug treatments are available for the symptomatic relief of neuropathic pain symptoms, these agents do not provide satisfactory relief in all patients. For these patients, other treatment alternatives such as combination drug therapy that produces pain relief via distinctly different mechanisms may be successful. The purpose of this review is to compare the efficacy and limitations of currently available pharmacological treatments for the symptomatic relief of PHN and PDN, and to discuss the potential of combination therapy in PHN and PDN.

Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) is a form of prolonged cardiopulmonary bypass used to temporarily sustain cardiac and/or respiratory function in critically ill patients. Extracorporeal membrane oxygenation further complicates the management of critically ill patients who already have profound physiologic derangements with consequent altered pharmacokinetics. The purpose of this study is to identify and critically review the published literature describing pharmacokinetics in the presence of ECMO. This review revealed a dearth of data describing pharmacokinetics during ECMO in critically ill adults, with most of the available data originating in neonates. Of concern, the present data indicate substantial variability and a lack of predictability in drug behavior in the presence of ECMO. The most common mechanisms by which ECMO affects pharmacokinetics are sequestration in the circuit, increased volume of distribution, and decreased drug elimination. While lipophilic drugs and highly protein-bound drugs (eg, voriconazole and fentanyl) are significantly sequestered in the circuit, hydrophilic drugs (eg, β-lactam antibiotics, glycopeptides) are significantly affected by hemodilution and other pathophysiologic changes that occur during ECMO. Although the published literature is insufficient to make any meaningful recommendations for adjusting therapy for drug dosing, this review systematically describes the available data enabling clinicians to make conclusions based on available data. Furthermore, this review serves to highlight the need for well-designed and conducted clinical and laboratory-based studies to provide the data from which robust dosing guidance can be developed to improve clinical outcomes in this most unwell cohort of patients.