Kuo-Sheng Liu

Lipid nanoparticles with different oil/fatty ester ratios as carriers of buprenorphine and its prodrugs for injection

Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN>NLC>LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.

Prophylacticiv ondansetron reduces nausea, vomiting and pruritus following epidural morphine for postoperative pain control

PurposeTo evaluate the prophylactic effect of ondansetron on nausea and vomiting following epidural morphine for postoperative pain control.MethodsSeventy women (n = 35 in each group) undergoing abdominal total hysterectomy under epidural anesthesia were enrolled in this randomized, double-blinded, and placebo-controlled study. At the end of surgery, all patients received epidural morphine 3 mg for postoperative pain relief. Before morphine injection, the ondansetron group receivediv ondansetron 4 mg, whereas the placebo group received iv saline.ResultsPatients in the ondansetron group reported a lower frequency of total postoperative nausea and vomiting (22%) and lower frequency of rescue antiemetic request (12%) than those in the placebo group (52% and 39%, respectively;P < 0.05). In addition, ondansetron was associated with a reduced incidence of pruritus following epidural morphine (28% vs 58%;P < 0.05).ConclusionWe conclude that iv ondansetron 4 mg is effective in the prevention of nausea, vomiting, and pruritus following epidural morphine for postoperative pain control.RésuméObjectifÉvaluer l’effet prophylactique de l’ondansétron sur les nausées et les vomissements qui suivent l’administration péridurale de morphine analgésique postopératoire.MéthodeSoixante-dix femmes (n = 35 dans chaque groupe) devant subir une hystérectomie abdominale totale sous anesthésie péridurale ont participé à l’étude randomisée, en double aveugle et contrôlée contre placebo. À la fin de l’opération, toutes les patientes ont reçu une analgésie péridurale avec 3 mg de morphine. Avant l’injection de la morphine, 4 mg d’ondansétron iv ont été administrés dans le groupe ondansétron et une solution saline dans le groupe placebo.RésultatsLes patientes ayant reçu l’ondansétron ont présenté une plus faible fréquence de nausées et de vomissements postopératoires totaux (22 %) et ont demandé moins d’antiémétique de secours (12 %), comparées aux femmes du groupe placebo (52 % et 39 %, respectivement; P < 0,05). Aussi, l’ondansétron a été associé à une incidence réduite de prurit après l’administration péridurale de morphine (28 % vs 58%; P < 0,05).ConclusionL’administration iv de 4 mg d’ondansétron est efficace pour prévenir les nausées, les vomissements et le prurit qui suivent l’administration péridurale de morphine analgésique postopératoire.

Skin permeation of buprenorphine and its ester prodrugs from lipid nanoparticles: lipid emulsion, nanostructured lipid carriers and solid lipid nanoparticles

The aim of this study was to develop and characterize lipid nanoparticle systems for the transdermal delivery of buprenorphine and its prodrugs. A panel of three buprenorphine prodrugs with ester chains of various lengths was synthesized and characterized by solubility, capacity factor (log K′), partitioning between lipids and water and the ability to penetrate nude mouse skin. Colloidal systems made of squalene (lipid emulsion, LE), squalene + Precirol (nanostructured lipid carriers, NLC) and Precirol (solid lipid nanoparticles, SLN) as the lipid core material were prepared. Differential scanning calorimetry showed that the SLN had a more-ordered crystalline lattice in the inner matrix compared to the NLC. The particle size ranged from 220–300 nm, with NLC showing the smallest size. All prodrugs were highly lipophilic and chemically stable, but enzymatically unstable in skin homogenate and plasma. The in vitro permeation results exhibited a lower skin delivery of drug/prodrug with an increase in the alkyl chain length. SLN produced the highest drug/prodrug permeation, followed by the NLC and LE. A small inter-subject variation was also observed with SLN carriers. SLN with soybean phosphatidylcholine (SLN-PC) as the lipophilic emulsifier showed a higher drug/prodrug delivery across the skin compared to SLN with Myverol, a palmitinic acid monoglyceride. The in vitro permeation of the prodrugs occurred in a sustained manner for SLN-PC. The skin permeation of buprenorphine could be adjusted within a wide range by combining a prodrug strategy and lipid nanoparticles.

isobolographic Analysis of Epinephrine With Bupivacaine, Dextromethorphan, 3-methoxymorphinan, or Dextrorphan on Infiltrative Anesthesia in Rats : dose-response Studies

Background and Objectives: The aims of this study were to establish the potencies of epinephrine, bupivacaine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan and evaluate interactions of epinephrine with bupivacaine, dextromethorphan, 3‐methoxymorphinan, or dextrorphan as an infiltrative anesthetic. Bupivacaine, a common and long‐acting local anesthetic, was used as control. Methods: Dose‐dependent responses of epinephrine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan on cutaneous analgesia were compared with bupivacaine in rats. The interactions of drugs were evaluated via an isobolographic analysis. Results: We found that epinephrine, bupivacaine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan produced a dose‐dependent local anesthetic effect as infiltrative cutaneous analgesia. Relative potencies were epinephrine > bupivacaine > dextromethorphan > 3‐methoxymorphinan > dextrorphan (P < .01 for each comparison). Coadministration of bupivacaine with epinephrine produced a synergistic effect, and coadministration of dextromethorphan, 3‐methoxymorphinan, or dextrorphan with epinephrine produced an additive effect. Conclusions: Epinephrine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan are known to have local anesthetic effects as infiltrative cutaneous analgesia in rats. Epinephrine increased the potency of bupivacaine, but not dextromethorphan, 3‐methoxymorphinan, or dextrorphan as an infiltrative anesthetic. The cutaneous analgesic effects of adding epinephrine to dextromethorphan, 3‐methoxymorphinan, or dextrorphan, are similar to combinations of 2 local anesthetics.

Cutaneous Analgesia and Systemic Toxicity of Carbetapentane and Caramiphen in Rats

Background Caramiphen produces spinal anesthesia; caramiphen and carbetapentane have never been tested as infiltrative cutaneous analgesic. The aim of this study was to compare cutaneous analgesia of caramiphen and carbetapentane with bupivacaine and evaluated their central nervous system and cardiovascular toxicity. Methods After the blockade of cutaneous trunci muscle reflex with subcutaneous drug injections in rats, we evaluated the local anesthetic effect of carbetapentane and caramiphen on infiltrative cutaneous analgesia. After continuous intravenous infusion of equipotent doses of bupivacaine, carbetapentane, caramiphen, and saline, we observed mean arterial blood pressure and heart rate and monitored the onset time of seizure, apnea, and impending death. Results Carbetapentane and caramiphen acted like bupivacaine and elicited cutaneous analgesia in a dose-related fashion. On a 50% effective dose (ED50) basis, the ranks of potencies were bupivacaine (1.78 [1.52–2.07]) > carbetapentane (2.53 [2.38–2.77]) > caramiphen (3.60 [3.41–3.99]) (P < 0.01). At equianalgesic doses (ED25, ED50, ED75), the duration caused by carbetapentane or caramiphen was similar to that caused by bupivacaine. Under equipotent doses, the infusion time of carbetapentane or caramiphen required to cause seizure, apnea, and impending death was longer than that of bupivacaine (P < 0.05). The decline in mean arterial blood pressure and heart rate was slower with carbetapentane or caramiphen when compared with bupivacaine (P < 0.01 for the differences) at equipotent doses. Conclusions Carbetapentane and caramiphen were similar to bupivacaine at producing durations of cutaneous analgesia but were less likely than bupivacaine to induce central nervous system and cardiovascular systemic toxicity.

The Systemic Toxicity of Equipotent Proxymetacaine, Oxybuprocaine, and Bupivacaine During Continuous Intravenous Infusion in Rats

BACKGROUND: Although proxymetacaine and oxybuprocaine produce topical ocular and spinal anesthesia, they have never been tested as cutaneous anesthetics. We compared cutaneous analgesia of proxymetacaine and oxybuprocaine with bupivacaine and tested their central nervous system and cardiovascular toxicity. METHODS: After blockade of cutaneous trunci muscle reflex with subcutaneous injections, we evaluated the local anesthetic effect of proxymetacaine and oxybuprocaine on cutaneous analgesia in rats. After IV infusions of equipotent doses of oxybuprocaine, proxymetacaine, and bupivacaine, we observed the onset time of seizure, apnea, and impending death and monitored mean arterial blood pressure and heart rate. RESULTS: Proxymetacaine and oxybuprocaine acted like bupivacaine and produced dose-related cutaneous analgesia. On a 50% effective dose basis, the ranks of potencies were proxymetacaine > oxybuprocaine > bupivacaine (P < 0.01). Under equipotent doses, the infusion times of proxymetacaine or oxybuprocaine required to cause seizure, apnea, and impending death were longer than that of bupivacaine (P < 0.05). The decrease in mean arterial blood pressure and heart rate was slower with oxybuprocaine and proxymetacaine compared with bupivacaine (P < 0.05 for the differences) at equipotent doses. CONCLUSIONS: Oxybuprocaine and proxymetacaine were more potent at producing cutaneous anesthesia but were less potent than bupivacaine at producing central nervous system and cardiovascular toxicity.

Novel Depots of Buprenorphine Prodrugs Have a Long-Acting Antinociceptive Effect

An analgesic with a prolonged duration may be desirable in patients with long-lasting pain. In this study, we evaluated the antinociceptive effects and durations of action of three novel depots of buprenorphine esters buprenorphine propionate, enanthate, and decanoate given by IM injection, in rats. The pharmacokinetic profiles of buprenorphine in blood after IM injection of these depots were also evaluated. Antinociception was evaluated using the plantar test. Buprenorphine concentrations in blood were assayed using high-performance liquid chromatography. We found that the traditional form of buprenorphine HCl (in saline) produced a dose-related antinociceptive effect. A dose of 0.6 &mgr;mol/kg buprenorphine HCl (in saline) produced a significant antinociceptive effect lasting 5 h. The same dose of buprenorphine base, propionate, enanthate, and decanoate (in oil) also produced a significant antinociceptive effect with longer durations of action of 26, 28, 52, and 70 h, respectively. The pharmacokinetic studies demonstrated that all the buprenorphine esters were prodrugs of buprenorphine. We conclude that the novel depots of buprenorphine prodrugs: buprenorphine propionate, enanthate, and decanoate produced a long-acting antinociceptive effect after IM injection in rats.

Impact of Ester Promoieties on Transdermal Delivery of Ketorolac

Different types of ketorolac ester prodrugs incorporating tert-butyl (KT), benzyl (KB), heptyl (KH), and diketorolac heptyl (DKH) promoieties were synthesized for the comparison of percutaneous penetration. The prodrugs were characterized according to their melting point, capacity factor, lipophilicity, solubility in 30% ethanol/buffer, enzymatic hydrolysis, in vitro skin permeation, hair follicle accumulation, and in vivo skin tolerance. Interactions between the prodrugs and esterases were predicted by molecular docking. Both equimolar suspensions and saturated solutions in 30% ethanol/pH 7.4 buffer were employed as the applied dose. All of the prodrugs exhibited a lower melting point than ketorolac. The lipophilicity increased in the following order: ketorolac < KT < KB < KH < DKH. The prodrugs were rapidly hydrolyzed to the parent drug in esterase medium, skin homogenate, and plasma, with KT and KB exhibiting higher degradation rates. KT exhibited the highest skin permeation, followed by KB. The flux of KT and KB exceeded that of ketorolac by 2.5-fold and twofold, respectively. KH and DKH did not improve ketorolac permeation but exhibited a sustained release behavior. KT and KH revealed selective absorption into follicles and a threefold greater follicular uptake compared with ketorolac. KB, KH, and DKH slightly but significantly increased transepidermal water loss (TEWL) after consecutive administration for 7 days, whereas ketorolac and KT exhibited no influence on TEWL. According to the experimental results, it can be concluded that an optimal balance between lipophilicity and aqueous solubility is important in the design of a successful prodrug. The acceptable skin tolerance for safe application is also an important consideration.

Combined strategies of apomorphine diester prodrugs and nanostructured lipid carriers for efficient brain targeting

Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

Epinephrine as adjuvant for propranolol produces a marked peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats

The aim of this study was to evaluate the effect of epinephrine as additive for propranolol as an infiltrative anesthetic. Using a rat model of cutaneous trunci muscle reflex (CTMR), we tested the effect of co-administration of epinephrine with propranolol on infiltrative cutaneous analgesia. Bupivacaine, a long-lasting local anesthetic, was used as control. Subcutaneous propranolol and bupivacaine elicited a dose-dependent local anesthetic effect on infiltrative cutaneous analgesia. On the 50% effective dose (ED50) basis, the relative potency was bupivacaine [2.05 (1.95-2.21) μmol/kg]>propranolol [9.21 (9.08-9.42) μmol/kg] (P<0.01 for each comparison). Subcutaneous epinephrine (0.012 μmol/kg) did not produce cutaneous analgesia. Mixtures of epinephrine (0.012 μmol/kg) with drugs (propranolol or bupivacaine) at ED50 or ED95, respectively, intensified and prolonged drug action on infiltrative cutaneous analgesia. Intraperitoneal injection of combined drugs (propranolol or bupivacaine) at ED95 with epinephrine (0.012 μmol/kg) exhibited no cutaneous analgesia. We concluded that propranolol was less potent but produced a similar duration of action when compared to bupivacaine on infiltrative cutaneous analgesia. Epinephrine as adjuvant for propranolol or bupivacaine enhanced the potency and extended the duration of action on infiltrative cutaneous analgesia.