Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose.

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects. The orvinol series of ligands are known for their high-affinity binding to opioid receptors and often extended duration of action; generally, compounds on this scaffold show agonist activity at the kappa and the mu-opioid receptor. Diprenorphine is an unusual member of this series being an antagonist at mu and only a partial agonist at kappa-opioid receptors. In this study, an orvinol antagonist, 14, was designed and synthesized that shows no agonist activity in vitro and is at least as good as naloxone at reversing the effects of mu-opioid receptor agonists in vivo.

Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan® ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half-life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long-lasting, non-surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist-inhibition of cAMP production was time-dependent, non-surmountable and non-reversible, consistent with (pseudo)-irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist-mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration-response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand-dependent manner. The shift in the [D-Ala2 ,N-MePhe4 ,Gly-ol5 ]-enkephalin (DAMGO) concentration-response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)-irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists.

Countermeasures for Preventing and Treating Opioid Overdose.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic "nanosponge" decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder.

Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys.

RATIONALE: Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. OBJECTIVE: This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. RESULTS: Neither MCAM (0.32 mg/kg) nor morphine (1-5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01-0.056 mg/kg) and phencyclidine (0.1-0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. CONCLUSIONS: MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys.

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.

Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats.

A novel µ-opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1-10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund's adjuvant). Before MCAM, morphine, fentanyl, and the κ-opioid receptor agonist spiradoline dose dependently increased tail-withdrawal latency from 50°C water; MCAM attenuated the antinociceptive effects of morphine and fentanyl, but not spiradoline. Morphine increased sensitivity to mechanical stimulation and decreased gastrointestinal motility, and MCAM blocked both effects. These antagonist effects of 10 mg/kg MCAM were persistent, lasting for 2 weeks or longer. Withdrawal emerged after discontinuation of morphine treatment or administration of 10 mg/kg MCAM or 17.8 mg/kg naloxone; other than the day of antagonist administration when withdrawal signs were greater in rats that received antagonist compared with rats that received vehicle, there was no difference among groups in directly observable withdrawal signs or decreased body weight. These results confirm that MCAM is a selective µ-opioid receptor antagonist with an exceptionally long duration of action, likely due to pseudoirreversible binding. Despite its sustained antagonist effects, the duration of withdrawal precipitated by MCAM is not different from that precipitated by naloxone, suggesting that the long duration of antagonism provided by MCAM could be particularly effective for treating opioid abuse and overdose. SIGNIFICANCE STATEMENT: The opioid receptor antagonist MCAM attenuates some abuse-related and toxic effects of opioids. This study demonstrates that MCAM selectively antagonizes multiple effects mediated by µ-opioid receptor agonists for 2 weeks or longer, and like naloxone, MCAM precipitates withdrawal in morphine-dependent rats. Despite this persistent antagonism, withdrawal signs precipitated by MCAM are not significantly different from signs precipitated by naloxone or occurring after discontinuation of morphine, suggesting that using MCAM for opioid abuse or overdose would not produce sustained withdrawal.

Long-Lasting Effects of Methocinnamox on Opioid Self-Administration in Rhesus Monkeys.

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n = 5) or cocaine (n = 4) under a fixed-ratio schedule. Another group (n = 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n = 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.

Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel µ-Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys.

One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory-depressant effects (minute volume [VE]) of heroin in five monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared with those of naltrexone (0.032 mg/kg). Heroin dose dependently decreased VE MCAM and naltrexone prevented respiratory depression, shifting the heroin dose-effect curve rightward at least 10-fold. MCAM, but not naltrexone, attenuated these effects of heroin for 4 days. MCAM (0.1-0.32 mg/kg) was given 30 minutes after heroin to determine whether it reverses respiratory depression; heroin dose-effect curves were generated 1, 2, 4, 8, and 16 days later, and these effects were compared with those of naloxone (0.0032-0.1 mg/kg). MCAM and naloxone reversed respiratory depression within 30 minutes, although only MCAM antagonized heroin on subsequent days. Thus, MCAM prevents and reverses respiratory depression, the potentially lethal effect of heroin, longer than opioid receptor antagonists currently in use. Because of its sustained effects, MCAM might provide more effective rescue from and protection against the fatal respiratory-depressant effects of opioids, thereby improving treatment of opioid overdose.

The novel µ-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception.

BACKGROUND AND PURPOSE: PZM21 is a novel µ-opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical µ receptor ligands such as morphine. We have re-examined the signalling profile of PZM21 and its ability to depress respiration. EXPERIMENTAL APPROACH: G protein (Gi ) activation and arrestin-3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing µ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole-body plethysmography, and antinociception was measured by the hot plate test. KEY RESULTS: PZM21 (10-9 - 3 × 10-5  M) produced concentration-dependent Gi activation and arrestin-3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10-80 mg·kg-1 ) depressed respiration in a dose-dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a decrease in tidal volume. On repeated daily administration of PZM21 (twice daily doses of 40 mg·kg-1 ), complete tolerance developed to the antinociceptive effect of PZM21 over 3 days but no tolerance developed to its respiratory depressant effect. CONCLUSION AND IMPLICATIONS: These data demonstrate that PZM21 is a low efficacy µ receptor agonist for both G protein and arrestin signalling. Contrary to a previous report, PZM21 depresses respiration in a manner similar to morphine, the classical opioid receptor agonist.

Psychosocial variables are associated with being wait-listed, but not with receiving a kidney transplant in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Psychosocial factors are associated with clinical outcomes in patients with end-stage renal disease. It is not known if self-reported depression and quality of life influence the likelihood of being wait-listed and receiving a transplant. METHODS: Prevalent cross section of 18- to 65-year-old hemodialysis (HD) patients in the USA (N = 2033) and seven European countries (N = 4350) from the Dialysis Outcomes and Practice Patterns Study phase II and III was analyzed. Wait-listed patients (N = 1838) were followed until kidney transplantation. Self-reported depressive symptoms were assessed by the Center for Epidemiologic Studies-Depression scale, 10-item version (CES-D) and health-related quality of life (HR-QoL) by the Kidney Disease Quality of Life Short Form 12 scale Physical Component Score (PCS). RESULTS: At study entry, 27% (USA) to 53% (UK) of patients were wait-listed in participating countries. Variables associated with lower odds of being on the waiting list included worse HR-QoL, more severe depressive symptoms, older age, fewer years of education, lower serum albumin, lower hemoglobin, shorter time on dialysis and presence of multiple comorbid conditions. Among wait-listed patients, significantly lower transplantation rates were seen for females, blacks, patients having prior transplantation and multiple comorbid conditions but not PCS or CES-D. CONCLUSIONS: Fewer depressive symptoms and better HR-QoL are associated with being on the waiting list in prevalent HD patients but not with receiving a kidney transplant among wait-listed dialysis patients. Regular assessment of subjective well-being may help identify patients with reduced access to wait-listing and kidney transplantation.

Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy.

Using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS), we determined incidence, prevalence, and outcomes among hemodialysis patients with atrial fibrillation. Cox proportional hazards models, to identify associations with newly diagnosed atrial fibrillation and clinical outcomes, were stratified by country and study phase and adjusted for descriptive characteristics and comorbidities. Of 17,513 randomly sampled patients, 2188 had preexisting atrial fibrillation, with wide variation in prevalence across countries. Advanced age, non-black race, higher facility mean dialysate calcium, prosthetic heart valves, and valvular heart disease were associated with higher risk of new atrial fibrillation. Atrial fibrillation at study enrollment was positively associated with all-cause mortality and stroke. The CHADS2 score identified approximately equal-size groups of hemodialysis patients with atrial fibrillation with low (less than 2) and higher risk (more than 4) for subsequent strokes on a per 100 patient-year basis. Among patients with atrial fibrillation, warfarin use was associated with a significantly higher stroke risk, particularly in those over 75 years of age. Our study shows that atrial fibrillation is common and associated with elevated risk of adverse clinical outcomes, and this risk is even higher among elderly patients prescribed warfarin. The effectiveness and safety of warfarin in hemodialysis patients require additional investigation.

The burden of amputation among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Hemodialysis patients are at increased risk of amputation, particularly those with diabetes. Limited data exist about the prevalence, incidence, risk factors for, and sequelae of amputation in hemodialysis patients. STUDY DESIGN: A prospective observational study of hemodialysis practices and outcomes. SETTING & PARTICIPANTS: Data from 29,838 patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from 1996 to 2004 were analyzed. PREDICTOR/FACTOR: Demographic factors, comorbid conditions, laboratory values, years since end-stage renal disease onset, and currently prescribed medications at study enrollment. OUTCOME: Prior amputation at study enrollment by using logistic regression and amputation during follow-up by using Cox models. Amputation was ascertained from medical record review. RESULTS: There was a high prevalence (6%) and incidence (2.0 events/100 patient-years at risk) of amputation in hemodialysis patients; patients with diabetes had a more than 9 times greater incidence of new amputation. Wide variations among countries were observed in risk of amputation, with the lowest prevalence in Japan and the highest in Belgium, France, and Germany. Traditional cardiovascular risk factors, such as age, peripheral vascular disease, and smoking were predictive of amputation, as were such risk factors related to hemodialysis as altered mineral metabolism and years of hemodialysis therapy. In patients with diabetes, greater relative risks of amputation were observed in men, smokers, and those with other diabetic complications, anemia, and malnutrition. The relative risk of mortality after amputation was 1.54 (95% confidence interval, 1.41 to 1.68; P < 0.001) with a mean survival of 2.0 versus 3.8 years. LIMITATIONS: The database does not differentiate between types of amputations; some amputations may have concerned the upper limbs and could have been linked to ischemia related to vascular access. CONCLUSIONS: Amputation in hemodialysis patients is a very frequent event, particularly in patients with diabetes, and is associated with both traditional cardiovascular risk factors and factors linked to kidney failure treated by hemodialysis. Interventional trials are needed to reduce the burden of amputation.

Successful treatment of pulmonary mucormycosis in a renal transplant recipient with limited pulmonary reserve by combined medical and surgical therapy.

Mucormycosis is a rare opportunistic fungal infection in renal transplant recipients which is associated with exceedingly high mortality when inadequately treated. Risk factors for this infection include diabetes, neutropaenia and immunosuppression. We report a case of pulmonary mucormycosis in a renal allograft recipient with type 2 diabetes and limited pulmonary reserve. The patient was successfully treated with lobectomy and liposomal amphotericin B with preservation of pulmonary and allograft functions. Early recognition of this infection is warranted before dissemination, which carries a poor prognosis.

A randomised, cross-over study comparing injection site pain with subcutaneous epoetin beta and subcutaneous darbepoetin alfa in patients with chronic kidney disease.

OBJECTIVE: To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease. RESEARCH DESIGN AND METHODS: This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30 mug or weekly sc epoetin beta 6000 IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10 cm ungraduated visual analogue scale (0 = no pain, 10 = worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed. TRIAL REGISTRATION: http://clinicaltrials. gov/(NCT00377481). RESULTS: All randomised patients (N = 48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score = 2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p < 0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p < 0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p < 0.001); 25% of patients reported no preference. CONCLUSIONS: Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful.

Bilateral basal ganglia lesions in patients with end-stage diabetic nephropathy.

Acute movement disorder associated with reversible bilateral basal ganglia lesions is an increasingly recognized syndrome in patients with end-stage renal disease, especially in the setting of concurrent diabetes mellitus. We report an elderly man with end-stage diabetic nephropathy treated by daily automated peritoneal dialysis who developed subacute symptoms of gait disturbance, dysarthria, dysphagia and lethargy. Computed tomography and magnetic resonance imaging of the head revealed bilateral symmetrical basal ganglia lesions. Repeat imaging 3 weeks later showed that these lesions had regressed spontaneously. However, his neurological symptoms improved slowly. These findings were similar to 23 other cases in the literature. Review of these cases shows that clinical features were predominantly bradykinesia, gait disturbance and concurrent metabolic acidosis (observed in 90% of cases). The pathogenesis of this condition has not been clearly defined, but uraemia may be an aggravating factor in predisposed patients, particularly in the presence of diabetic microvascular disease. There is no specific treatment for this condition; supportive measures are the mainstay of management. In the majority of patients, neurological improvement lags behind regression of basal ganglia lesions seen with neuroimaging, and the long-term outcome is variable.

Extended dosing intervals with erythropoiesis-stimulating agents in chronic kidney disease: a review of clinical data.

The recombinant human erythropoietins epoetins alfa and beta have relatively short half-lives ( approximately 24 h by subcutaneous route) and have traditionally been administered 2 or 3 times a week for the treatment of anaemia in patients with chronic kidney disease. However, multiple weekly injections are inconvenient for both the patient and the healthcare provider. With the introduction of the longer-acting erythropoiesis-stimulating agent darbepoetin alfa, there has been growing interest in longer dosing intervals for erythropoiesis-stimulating agents. Data from several randomized studies have shown that darbepoetin alfa is effective in maintaining haemoglobin levels when administered (subcutaneously, intravenously or both) every 2 weeks in dialysis patients, and every 2 weeks or monthly in patients with chronic kidney disease not yet receiving dialysis. Moreover, intravenous administration with darbepoetin alfa does not require a higher dosage compared with the subcutaneous route. Epoetins alfa and beta have also been studied in similar schedules, although few data from well-designed studies are available. Current data suggest that once-weekly administration of these forms of epoetin is feasible in dialysis patients, but dose increases are often required when switching patients from traditional twice- or thrice-weekly schedules. Also, administration of epoetins every other week is feasible in selected patients with chronic renal insufficiency. Further study is required to clarify the optimum schedule for epoetins in these settings.

Darbepoetin alfa administered monthly maintains haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis: a multicentre, open-label, Australian study.

AIM: Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W). METHODS: This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrollment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb >or= 100 g/L during the evaluation period (weeks 21-33). RESULTS: Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb >or= 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 microg. Darbepoetin alfa was considered to be well-tolerated. CONCLUSION: Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.

Randomized cross-over comparison of intravenous and subcutaneous darbepoetin dosing efficiency in haemodialysis patients.

BACKGROUND: Studies have consistently shown the superior dosing efficiency of subcutaneous (s.c.) compared to intravenous (i.v.) erythropoietin (r-HuEPO). Unlike r-HuEPO, data from pivotal darbepoetin trials support s.c. and i.v. dosing equivalence, however, no blinded cross-over randomized studies of s.c. and i.v. dose efficiency or intra-patient variability in response have been published. METHODS: During this 12-month study, 53 haemodialysis patients were randomized to s.c. or i.v. darbepoetin for a 6-month period and then switched to the alternative route for a second 6-month period. Darbepoetin dose was titrated during the first 4-months of each period to achieve a stable haemoglobin during the final 2-month observation period of each arm. RESULTS: Twenty-four patients were included in analysis. No significant difference between s.c. and i.v. administration was observed for any measured parameter. Patients achieved a non-significantly higher haemoglobin (123.6 +/- 3.76 vs 120.9 +/- 4.42 g/L, P = 0.11) from a non-significantly lower darbepoetin dose (40.8 +/- 10.7 vs 42.5 +/- 11.0 mcg/week, P = 0.23) with i.v. administration. The population-based weight normalized s.c./i.v. dose ratio was 1.04 (0.97-1.11). Despite no significant overall difference, some patients experienced changes in individual dose efficiency response. Three of 24 patients recorded a greater than 30% change, four of 24 recorded between a 20 and 30% change, and five of 24 patients recorded between a 10 and 20% change relative to i.v. dose efficiency. CONCLUSIONS: This study further supports s.c. and i.v. dosing equality and that overall the more convenient i.v. route can be used with equal dosing efficiency. However, patients switching routes of administration should be monitored due to the wide range in individual response.

Vascular access results from the Dialysis Outcomes and Practice Patterns Study (DOPPS): performance against Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines.

BACKGROUND: The Kidney Disease Outcomes Quality Initiative Guidelines for Vascular Access in hemodialysis patients recommend native arteriovenous (AV) fistulae over AV grafts or catheters for permanent vascular access. They recommend letting fistulae mature > or =1 month before cannulation. METHODS: The Dialysis Outcomes and Practice Patterns Study (DOPPS) provides an unparalleled means to examine vascular access practice patterns and guidelines internationally, with particular attention to associations with mortality risk. RESULTS: Most patients in Europe and Japan dialyze through AV fistulae and very few use AV grafts; in the United States, more patients use grafts than fistulae. Patients who receive nephrologic care for over 30 days before starting dialysis have significantly higher chances of commencing via AV fistula. Medical directors of dialysis facilities in the United States commonly prefer grafts; in Europe and Japan, most prefer fistulae. In the United States, there is a relatively long average time between fistula creation and cannulation but significantly worse fistula survival than that seen in Europe. Tunneled catheters pose a higher mortality risk than permanent accesses and are associated with increased risk of failure of a subsequent fistula. The percentage of prevalent patients in the DOPPS countries using catheters has increased in recent years. DOPPS data suggest that performance in some countries falls short of practices achieved in other countries. AV fistula use is low in the United States but has been improving. The trend of increasing use of catheters in most countries is discouraging. CONCLUSION: The DOPPS will continue to monitor practice trends and explore whether greater application of guidelines will lead to fewer access complications and improved longevity for hemodialysis patients.