Design of pediatric oral formulations with a low proportion of methadone or phenobarbital for the treatment of neonatal abstinence syndrome.

CONTEXT: Elaboration of oral liquid formulations is the best alternative when no marketed forms are available for pediatrics. OBJECTIVE: The development, characterization and stability evaluation of methadone (MI, MII, MIII) and phenobarbital (PI, PII) can be used for the treatment of neonatal abstinence syndrome (NAS). MATERIAL AND METHODS: A standard operating procedure was established and parameters such as appearance, pH, rheological behavior and drug content were evaluated at three temperatures for 90 days. RESULTS AND DISCUSSION: Changes in color of phenobarbital made necessary the storage below 25 °C. pH did not change in methadone solutions and was able to maintain phenobarbital solubilized. Degradation data at 4 °C fitted to Plateau equation followed by one phase decay. MI was stable for 60 days at the three temperatures; MII for 90 days at 4 and 25 °C and 60 days at 40 °C; MIII for 60 days at 4 °C, 15 days at 25 °C and 7 days at 4 °C. PI was stable for 60 days at 4 °C and 30 days at 25 °C. PII was stable for 7 days at 4 and 25 °C. All solutions met microbial specifications. CONCLUSION: A correct dosage for the treatment of NAS was guaranteed.

Usos clínicos de la metadona / Clinical uses of methadone

La metadona es un opioide sintético agonista total en receptores micro, y antagonista de los receptores NMDA. Es altamente liposoluble, con una vida media de unas 23 horas, pudiendo variar entre 13 y 54 horas. Es un isómero óptico, cuya forma L es la responsable de la mayor actividad analgésica. Este fármaco ha sido utilizado satisfactoriamente desde hace años para el tratamiento sustitutivo de pacientes drogodependientes, sin embargo, su utilización como analgésico es menos generalizada, a pesar de su perfil farmacológico que podría ser beneficioso en este aspecto. Teniendo esto en cuenta, hemos revisado las principales aplicaciones terapéuticas de la metadona, y su implicación tanto en el dolor agudo como en el dolor crónico. La metadona es una alternativa atractiva para el tratamiento del dolor oncológico y neuropático, dada su buena disponibilidad oral, su larga vida media con escasas dosis diarias y su bajo coste. Las vías intravenosa, intradural, y epidural, se han mostrado eficaces y seguras para el tratamiento del dolor posoperatorio

Methadone is a synthetic opioid that is primarily a micro-opioid agonist, but also a NMDA-antagonist. It is highly liposoluble and has an average lifee in blood of approximately 23 hours, although it can vary from 13 to 54 hours. It is an optical isomer, where l-methadone is the primarily responsible factor for the analgesic effect. Methadone has successfully been used for many years for the treatment of dependence on opioid drugs. However, it has been less used as an analgesic, in spite of its useful pharmacolog ic profile. Bearing this in mind, we have reviewed the main therapeutic uses of methadone, and its effectiveness in treating both acute and chronic pain. Methadone is an attractive alternative for the treating cancer and neuropathic pain, because of its good oral bioavailability, its long average lHe at low daily doses and its oral bioavailability, its long average life at low daily doses and its low cost. Intravenous, intrathecal and epidural viae have shown to be effective and safe for the treatment of postoperative pain

Selective antibodies to methadone enantiomers: synthesis of (R)- and (R,S)-methadone conjugates and determination by an immunoenzymatic method in human serum.

Selective antibodies to (R)-methadone (Mtd) and to its racemate were produced in rabbits by immunization with conjugates of (R)- or (R,S)-hemisuccinyl-methadol-bovine serum albumin, respectively. A hapten was first prepared by reduction of (R)- or (R,S)-Mtd with sodium borohydride, followed by esterification with succinic anhydride. The conjugation of hapten with albumin was achieved by the mixed anhydride method. After immunization of rabbits, the titers and specificity of each antibody were determined by ELISA. The antibodies obtained were tested with (R)-, (S)-, (R,S)-Mtd, its major metabolite (EDDP), and some drugs of abuse (morphine, codeine, cocaine). The sensitivities of antibodies to (R)- and (R,S)-Mtd were about 1 and 2 ng/ml, respectively. Selective (R)-antibodies recognized (R)-Mtd about 40 times more avidly than the (S)-isomer, while an antiserum against (R,S)-Mtd recognized (R)- and (S)-isomers to about the same degree. Both selective antibodies showed little interference (about 0.5%) with EDDP metabolite and no crossreactivity with morphine, codeine, and cocaine. These two selective antibodies were used to develop an immunoenzymatic method (ELISA) for the determination of (R)- and (R,S)-Mtd in serum samples of patients under maintenance treatment for narcotic addiction.

Phenyl-substituted normethadones: synthesis and pharmacology.

Phenyl-substituted normethadone derivatives were synthesized and their affinity (IC50) for opioid receptors was determined by displacement of the specific binding sites of [3H]sufentanyl on rat brain preparations. Substitution resulted in a decrease of affinity in-vitro. These results suggest that normethadone-like compounds may interact with the P subsite of the mu-opioid receptor and that the P subsite has a well-defined cavity shape of stringent dimensions.

Synthesis, characterization, and quantitation of para-hydroxymethadone, a metabolite of methadone in the rat.

To demonstrate a p-hydroxylation process in the metabolism of methadone, we have synthesized para-hydroxymethadone and characterized it by spectroscopy (IR, 13C-NMR, mass spectrometry) and chromatography (thin layer chromatography, gas-liquid chromatography, and HPLC). para-Hydroxymethadone was isolated by HPLC from the urine of rats treated with (R,S)-methadone. para-Hydroxymethadone in the urine and in the bile represents 1.82 and 38.08%, respectively, of the administered dose. para-Hydroxymethadone does not exhibit any opioid-like activity.

Synthesis, X-ray crystallographic determination, and opioid activity of erythro-5-methylmethadone enantiomers. Evidence which suggests that mu and delta opioid receptors possess different stereochemical requirements.

Enantiomers of erythro-5-methylmethadone (3) were synthesized from optical antipodes of erythro-3-(dimethyl-amino)-2-butanol. X-ray crystallographic analysis of (-)-3 perchlorate revealed that it possesses the 5S,6S absolute configuration. It was found that (-)-3 is substantially more potent than its enantiomer (+)-3 as an opioid agonist in vivo and in vitro. In vitro tests (guinea pig ileal longitudinal muscle and mouse vas deferens preparations) suggest that (-)-3 mediates its effect chiefly through mu opioid receptors. On the other hand, (+)-3 and the more potent enantiomers of methadone, (-)-1, and isomethadone, (-)-2, appear to have less mu-receptor selectivity and interact with a greater fraction of delta receptors than does (-)-3. The fact that the solid-state conformation of (-)-3 differs from that of (-)-1 and (-)-2, which show great similarity in conformational features, suggests that mu and delta receptors have different conformational requirements. The possibility of different modes of interaction with a single opioid receptor population also is discussed.

Synthesis and analgesic activity of some long-acting piperidinospiro derivatives of methadone.

A congener of methadone, in which the metabolically labile C-6 dimethylamino moiety was replaced with a piperidinospiro derivative, was reduced and acetylated. This conversion produced a marked increase in the duration of analgesia, a trend similar to that found for methadone.

Quantitative analysis of methadone in biological fluids using deuterium-labeled methadone and GLC-chemical-ionization mass spectrometry.

The (+)-,(-)-, and (+/-)-2H5-methadones, which contained five deuterium atoms in one aromatic ring, were synthesized for use in clinical pharmacological studies and as internal standards. GLC-chemical-ionization mass spectrometry was used to determine plasma and urinary methadone levels by an inverse isotope dilution assay. Plasma drug levels could be determined to 10 pmoles/ml, and urine levels could be measured to 5 pmoles/ml. Plasma methadone levels were examined in several patients undergoing methadone maintenance therapy. These levels generally ranged between 100 and 400 ng/ml (320-1300 pmoles/ml) after an average oral dose of 1 mg/kg/day. The methadone half-life was 28.8 +/- 4.8 hr.

Methadone salts. Part 1: preparation and identification.

The preparation of two methadone salts, namely: methadone-alpha-naphthalenesulfonate and methadone-o-benzoyl-benzoate is described. The prepared compounds were confirmed by t.l.c. and IR spectroscopic studies.

Stereochemical studies on medicinal agents. 21. Investigation of the role of conformational factors in the action of diphenylpropylamines. Synthesis and analgetic potency of 5-methylmethadone diastereomers.

The synthesis of racemic threo- and erythro-5-methylmethadone (3a and 3b, respectively) was carried out and the solution conformation of each isomer was investigated through pKa and NMR studies. The data indicate that 3a-HCl exists exclusively in an internally hydrogen-bonded conformation while the erythro isomer 3b-HCl is present as a mixture of conformations. The erythro racemate 3b was found to possess 5.4 times the analgetic potency of (+/-)-methadone in contrast to the threo racemate 3a which was inactive and devoid of antagonist activity. The fact that the inactive racemate 3a contains the 5S,6R stereoisomer, which combines the configurations found in the more active enantiomers of methadone and isomethadone, suggests that the chiral centers do not behave as independent units and that conformational factors are playing an important role in governing stereoselectivity. These results, when analyzed together with earlier reports, suggest that one of the pharmacophoric conformations of the diphenylpropylamine analgetics possesses an antiperiplanar-like disposition of the Ph2CCOEt and +NHMe2 groups.

Synthesis of a new metabolite of acetylmethadol.

The primary amine metabolites of alpha-(plus or minus)- alpha-(minus)-acetylmethadol were synthesized. A neutral permanganate oxidation of noracetylmethadol gave a nitroalkane. This unusual oxidation product was readily converted to the primary amine metabolite of acetylmethadol.