Olga Vlagislavovna Lopatko

Evolution of surface activity related functions of vertebrate pulmonary surfactant.

1. Pulmonary surfactant is a mixture of lipids and proteins that lines the air‐liquid interface of the lungs of all vertebrates. In mammals, it functions to reduce and vary surface tension, which helps to decrease the work of breathing, provide alveolar stability and prevent alveolar oedema. The present review examines the evolution and relative importance of these surface activity related functions in the lungs of vertebrates.

Opioid maintenance: a comparative review of pharmacological strategies

The use of opioids outside of medical practice is a significant health problem with important social and political implications. Although treatment of opioid dependence is traditionally focused on heroin users, there is increasing recognition that a large number of people become dependent through the use of prescription opioids. The necessity for long-term treatment has also been increasingly recognised. At present, there are several pharmacotherapies available for maintenance treatment, including drugs that are full agonists at the opioid receptor (e.g., methadone, slow-release oral morphine), a partial agonist (buprenorphine) and an opioid antagonist (naltrexone). This review examines the existing strategies, highlights problems associated with their use and discusses the opportunities for new treatment approaches, particularly the use of long-acting formulations.

Control of pulmonary surfactant secretion from type II pneumocytes isolated from the lizard Pogona vitticeps

Pulmonary surfactant, a mixture consisting of lipids and proteins and secreted by type II cells, functions to reduce the surface tension of the fluid lining of the lung, and thereby decreases the work of breathing. In mammals, surfactant secretion appears to be influenced primarily by the sympathetic nervous system and changes in ventilatory pattern. The parasympathetic nervous system is not believed to affect surfactant secretion in mammals. Very little is known about the factors that control surfactant secretion in nonmammalian vertebrates. Here, a new methodology for the isolation and culture of type II pneumocytes from the lizard Pogona vitticeps is presented. We examined the effects of the major autonomic neurotransmitters, epinephrine (Epi) and ACh, on total phospholipid (PL), disaturated PL (DSP), and cholesterol (Chol) secretion. At 37°C, only Epi stimulated secretion of total PL and DSP from primary cultures of lizard type II cells, and secretion was blocked by the β-adrenoreceptor antagonist propranolol. Neither of the agonists affected Chol secretion. At 18°C, Epi and ACh both stimulated DSP and PL secretion but not Chol secretion. The secretion of surfactant Chol does not appear to be under autonomic control. It appears that the secretion of surfactant PL is predominantly controlled by the autonomic nervous system in lizards. The sympathetic nervous system may control surfactant secretion at high temperatures, whereas the parasympathetic nervous system may predominate at lower body temperatures, stimulating surfactant secretion without elevating metabolic rate.

Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine

In maintenance patients methadone has been shown to produce considerable changes in opioid effects and withdrawal over the dosing interval. As a partial agonist buprenorphine may be expected to produce smaller changes, but the nature and magnitude of these changes have only been described for single doses. In the present study opioid effects and withdrawal were described in patients maintained on buprenorphine. Twenty four opioid dependent subjects were administered 16 mg buprenorphine tablets sublingually for 10 days. On day 10 plasma samples were collected and physiological, subjective and observer-rated measures collected pre-dose and at 14 time points during the dosing interval. No significant respiratory depression was observed. Consistent with the partial agonist properties of buprenorphine, other physiological and subjective changes were also of small magnitude. However, even at a once daily dose of 16 mg some patients experienced significant opioid withdrawal that was maximal at the end of the dosing interval. Buprenorphine maintenance should be associated with a high level of safety and a low level of disruption caused by changing opioid effects over the dosing interval, but some patients may require high doses or other strategies to completely suppress withdrawal.

Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone‐ and buprenorphine‐maintained subjects

AIMS To compare the O-demethylation (CYP2D6-mediated), N-demethylation (CYP3A4-mediated) and 6-glucuronidation (UGT2B4/7-mediated) metabolism of codeine between methadone- and buprenorphine-maintained CYP2D6 extensive metabolizer subjects. METHODS Ten methadone- and eight buprenorphine-maintained subjects received a single 60 mg dose of codeine phosphate. Blood was collected at 3 h and urine over 6 h and assayed for codeine, norcodeine, morphine, morphine-3- and -6-glucuronides and codeine-6-glucuronide. RESULTS The urinary metabolic ratio for O-demethylation was significantly higher (P= 0.0044) in the subjects taking methadone (mean ± SD, 2.8 ± 3.1) compared with those taking buprenorphine (0.60 ± 0.43), likewise for 6-glucuronide formation (0.31 ± 0.24 vs. 0.053 ± 0.027; P < 0.0002), but there was no significant difference (P= 0.36) in N-demethylation. Similar changes in plasma metabolic ratios were also found. In plasma, compared with those maintained on buprenorphine, the methadone-maintained subjects had increased codeine and norcodeine concentrations (P < 0.004), similar morphine (P= 0.72) and lower morphine-3- and -6- and codeine-6-glucuronide concentrations (P < 0.008). CONCLUSION Methadone is associated with inhibition of CYP2D6 and UGTs 2B4 and 2B7 reactions in vivo, even though it is not a substrate for these enzymes. Plasma morphine was not altered, owing to the opposing effects of inhibition of both formation and elimination; however, morphine-6-glucuronide (analgesically active) concentrations were substantially reduced. Drug interactions with methadone are likely to include drugs metabolized by various UGTs and CYP2D6.

(R)‐ and (S)‐methadone and buprenorphine concentration ratios in maternal and umbilical cord plasma following chronic maintenance dosing in pregnancy

AIMS The aim of this study was to compare the transfer of buprenorphine and methadone between maternal and cord blood in women under chronic dosing conditions and to determine if differences exist in the transfer of the two methadone enantiomers. METHODS Maternal and cord blood samples were collected at delivery from women maintained on methadone (35, 25-140 mg day⁻¹) (median; range) or buprenorphine (6.00, 2-20 mg day⁻¹) during pregnancy. Plasma concentration ratios are presented as an indicator of foetal exposure relative to the mother. RESULTS Methadone was quantified in all samples, with cord : maternal plasma methadone concentration ratios (n= 15 mother-infant pairs) being significantly higher (P < 0.0001; mean difference (MD) 0.07; 95% confidence interval (CI) 0.048, 0.092) for the active (R)-methadone enantiomer (0.41; 0.19, 0.56) (median; range) compared with (S)-methadone (0.36; 0.15, 0.53). (R)- : (S)-methadone concentration ratios were also significantly higher (P < 0.0001; MD 0.24 95% CI 0.300, 0.180) for cord (1.40; 0.95, 1.67) compared with maternal plasma (1.16; 0.81, 1.38). Half the infant buprenorphine samples were below the assay lower limit of quantification (LLOQ) (0.125 ng ml⁻¹). The latter was four-fold lower than the LLOQ for methadone (0.50 ng ml⁻¹). The cord : maternal plasma buprenorphine concentration ratio (n= 9 mother-infant pairs) was 0.35; 0.14, 0.47 and for norbuprenorphine 0.49; 0.24, 0.91. CONCLUSIONS The transfer of the individual methadone enantiomers to the foetal circulation is stereoselective. Infants born to buprenorphine maintained women are not exposed to a greater proportion of the maternal dose compared with methadone and may be exposed to relatively less of the maternal dose compared with infants born to women maintained on methadone during pregnancy.

Surfactant in the gas mantle of the snail Helix aspersa

Surfactant occurs in cyclically inflating and deflating, gas‐holding structures of vertebrates to reduce the surface tension of the inner fluid lining, thereby preventing collapse and decreasing the work of inflation. Here we determined the presence of surfactant in material lavaged from the airspace in the gas mantle of the pulmonate snail Helix aspersa. Surfactant is characterized by the presence of disaturated phospholipid (DSP), especially disaturated phosphatidylcholine (PC), lavaged from the airspace, by the presence of lamellated osmiophilic bodies (LBs) in the airspaces and epithelial tissue, and by the ability of the lavage to reduce surface tension of fluid in a surface balance. Lavage had a DSP/phospholipid (PL) ratio of 0.085, compared to 0.011 in membranes, with the major PL being PC (45.3%). Cholesterol, the primary fluidizer for pulmonary surfactant, was similar in lavage and in lipids extracted from cell homogenates (cholesterol/PL: 0.04 and 0.03, respectively). LBs were found in the tissues and airspaces. The surface activity of the lavage material is defined as the ability to reduce surface tension under compression to values much lower than that of water. In addition, surface‐active lipids will vary surface tension, increasing it upon inspiration as the surface area expands. By these criteria, the surface activity of lavaged material was poor and most similar to that shown by pulmonary lavage of fish and toads. Snail surfactant displays structures, a biochemical PL profile, and biophysical properties similar to surfactant obtained from primitive fish, teleost swim bladders, the lung of the Dipnoan Neoceratodus forsteri, and the amphibian Bufo marinus. However, the cholesterol/PL and cholesterol/DSP ratios are more similar to the amphibian B. marinus than to the fish, and this similarity may indicate a crucial physicochemical relationship for these lipids.

Ineffective morphine treatment regimen for the control of Neonatal Abstinence Syndrome in buprenorphine- and methadone-exposed infants

This study aimed to determine if morphine is effective in ameliorating Neonatal Abstinence Syndrome (NAS) symptoms to non-opioid-exposed control levels in methadone- and buprenorphine-exposed infants. A prospective, non-randomized comparison study with flexible dosing was undertaken in a large teaching maternity hospital in Australia. Twenty-five infants in the groups of buprenorphine-, methadone- and control non-opioid-exposed infants were compared (total n = 75 infants). Oral morphine sulphate (1 mg/ml) was administered every 4 h to opioid agonist-exposed infants. Modified Finnegan Withdrawal Scale (MFWS) scores determined dosing: score of 8-10: 0.5 mg/kg/day, 11-13: 0.7 mg/kg/day and 14+: 0.9 mg/kg/day. Withdrawal score, amount of morphine administered and length of hospital stay, were used to assess NAS over a 4-week follow-up period. No controls achieved a score higher than 7 on the MFWS. There was no significant difference in the percentage of infants requiring treatment between methadone (60%) and buprenorphine (48%) infants. For treated infants, significantly (P < 0.01) more morphine was administered to methadone (40.07 ± 3.95 mg) compared with buprenorphine infants (22.77 ± 4.29 mg) to attempt to control NAS. Following treatment initiation, significantly more (P < 0.01) methadone (87%) compared with buprenorphine infants (42%) continued to exceed scoring thresholds for morphine treatment requirement, and non-opioid-exposed control infant scores. For treated infants, there was no significant difference in length of hospital stay between methadone and buprenorphine infants. Morphine treatment was not entirely effective in ameliorating NAS to non-opioid-exposed control symptom levels in methadone or buprenorphine infants. The regimen may be less effective in methadone compared with buprenorphine infants.

Patterns of symptom reporting during pregnancy comparing opioid maintained and control women.

Objective:To characterize the range of symptoms experienced by pregnant methadone-maintained (MM) and buprenorphine-maintained (BM) women to determine whether these differ from those experienced by a control group of nonopioid exposed pregnant women. Opioid-maintained (OM) patients report high rates of symptoms related to direct opioid effects and withdrawal. Pregnancy is associated with a range of symptoms, some overlapping with opioid effects and withdrawal. Methods:Prospective, nonrandomized, open-label comparison study undertaken in a large teaching maternity hospital in South Australia. Pregnant BM (n = 25), MM (n = 25) and nonopioid exposed controls (n = 25) were recruited and matched for age, parity, gravidity, alcohol consumption, and smoking status. Symptom report patterns, maternal withdrawal, and additional substance use were assessed. Results:MM women reported 10 and BM women reported 2 symptoms throughout pregnancy at rates greater than controls. Methadone-maintained women reported significantly (P < 0.05) more symptoms than BM women compared to controls throughout pregnancy. Methadone-maintained women reported 8 and BM women reported 3 symptoms in the third trimester at rates greater than controls. Methadone-maintained women reported greater opioid withdrawal than controls; this did not occur in BM women. Additional substance use was comparable between BM and MM women but greater than controls. Conclusions:Patterns of symptom reports may have clinical implications for maternal and fetal health during pregnancy for OM women including optimization of opioid dosing regimens, education regarding maternal nutritional intake and preventing postnatal depression, thereby ensuring maternal health and fetal development during pregnancy and enhancing mother-infant bonding and healthy child development postnatally.