F. H. Field

Drug interactions with methadone.

Chronic methadone maintenance is now being used to treat over 85,000 heroin addicts in the United States alone. It is also being widely used throughout the world. It has been suggested anecdotally that various sedatives, tranquilizers, other depressants and stimulants including alcohol, diazepam, barbiturates, cocaine and amphetamines may have additive, potentiating, or antagonistic effects when taken by methadone maintenance patients. Few of these postulated drug interactions have been documented in human subjects on chronic methadone maintenance. None of these pharmacologic agents have been shown to alter methadone disposition in patients receiving methadone on a chronic basis, although certainly such drug interactions might be documented in the future. Two different types of drug interactions, both resulting in the same clinical picture of acute narcotic withdrawal, have been observed in methadone-maintained subjects. Both of these drug interactions have been studied to determine whether or not the clinical observations of narcotic withdrawal could be related to any alterations in methadone disposition. Gas liquid chromatography techniques developed in this laboratory and chemical ionization mass spectrometry techniques developed in the collaborative laboratory were used in this study for the quantitative and qualitative analyses of methadone and its metabolites in plasma, urine, and feces. Following oral administration and absorption, methadone is widely distributed in the body. Plasma levels are relatively low, even after a chronic daily maintenance dose of 50 to 100 m ~ . l ~ Methadone is metabolized primarily in the liver by the hepatic microsomal drug-metabolizing enzymes. In the major pathway of biotransformation, methadone is first N-demethylated and then undergoes cyclization to form its major pyrrolidine metabolite (FIGURE 1) .4

Fission fragment ionization (252Cf) mass spectrometry. Positive and negative spectra and decomposition mechanisms for seven compounds

The 252Cf fission fragment ionization mass spectra (both positive and negative ions) have been determined for alanine, arginine, sucrose, guanosine, 5′-adenosine monophosphate alanylalanylalanine, and lysyltyrosylthreonine. The lower m/z limit is 18 for the positive and 26 for the negative spectra tabulated. Mass to ion charge values are given with millimass precision, which permits deduction of atomic compositions for many of the observed ions. Reasonable mechanisms for the production of some of these ions are postulated. The significant findings of the study are: 1. (1) The amount of fragmentation occurring is large both in that quasi-molecular ion intensities are low and that many small ions are produced with large intensities. For example, only for alanine is the intensity of the quasi-molecular ion greater than 10% of the total ionization, and for arginine the CN− ion comprises 56% of the total negative ionization. 2. (2) The spectra observed have characteristically a quasi-molecular ion, a large gap without ions, and many ions at low mass. 3. (3) Detectable amounts of quasi-molecular ions are present in all the spectra. 4. (4) Reactions invoking known chemistry of gaseous positive and negative ions can be written for the formation of many of the fragment ions. 5. (5) The results indicate that the ionization process occurring is primarily a relatively high-energy one since it produces much fragmentation, but it has a low-energy component which is involved in the formation of the quasi-molecular ions observed here and in previosly published work. An ancillary finding is that the fission fragment ionization method seems to have a high sensitivity for producing anions from certain inorganic trace impurities.

Fission fragment ionization mass spectrometry: Metastable decompositions

Abstract Distorted peak shapes observed in 252Cf fission fragment ionization mass spectrometry using time-of-flight mass spectrometers are shown to result from delayed dissociations of initial ions. Decompositions occurring in the ion acceleration region produce tails on parent or fragment ion peaks, and decompositions occurring with the conversion of internal to kinetic energy in the field-free ion drift region produce broadenings of the parent ion peaks. In this work the various processes have been investigated by the application of appropriate retarding potentials. Examples of the various decomposition processes are given. The magnitudes of the internal energies converted are given for several processes. The application of suitable retarding potentials can be used to suppress decomposition products and enhance resolution and to determine the identities of the decomposition processes.

A rapid, sensitive mass spectrometric method for investigating microscale chemical reactions of surface adsorbed peptides and proteins

A new mass spectrometric method for measuring the products of reactions of surface adsorbed peptides and proteins is described. The technique is rapid, convenient, and sensitive and provides detailed information concerning the molecular weights of the reaction products and the rate and extent of reaction. The properties of the technique are illustrated by an investigation of cleavage reactions of the disulfide bonds in bovine insulin, cyclic somatostatin, and conotoxin G1 utilizing the reducing agent dithiothreitol.

Analyses of methadone and other drugs in maternal and neonatal body fluids: Use in evaluation of symptoms in a neonate of mother maintained on methadone

A former heroin addict treated with methadone maintenance throughout pregnancy, with rapid dose reduction from 110 mg to 9 mg during the last five weeks pre-partum, was evaluated in late pregnancy, at time of labor and delivery, and post-partum; her child was also evaluated. Using gas and thin-layer chromatography and mass spectroscopy, methadone levels were measured, and other drugs looked for in (1) plasma during late pregnancy, (2) mixed cord blood, (3) amniotic fluid at delivery, (4) maternal plasma and milk post-partum (on 50 mg methadone), (5) neonatal plasma and urine. Low levels of methadone were present in amniotic fluid and neonatal urine but not in mixed cord blood or neonatal plasma. Levels of methadone present in breast milk during moderate dose maintenance were also low. Unexpectedly, pentobarbital was identified in amniotic fluid. Neonatal infection was also diagnosed. Multiple factors may have contributed to symtoms observed in the neonate.

Fission fragment ionization mass spectrometry of alamethicin I

5157 transition-metal systems for their reactivity toward C02 through the use of C02(1). for the loan of the precious metal salts used in this work. This

Chemical ionization mass spectrometry

Chemical ionization mass spectrometry is a technique of mass spectrometry wherein the ionization of the substance of interest is effected by ion-molecule reactions rather than by electron impact, photon impact, or field ionization. The spectrum of a substance produced by chemical ionization is different from the spectra produced by the other ionization techniques, and the characteristic aspects of the chemical ionization spectrum are of analytical value and also of value in providing information about the ionic chemistry of the substance under investigation. Preliminary reviews of chemical ionization have been published.(1,2) The characteristic feature of the chemical ionization concept may be looked upon as the utilization of a specific set of ions to effect a specific type of ion-molecule reaction with a wide variety of different compounds. The ions produced by these ion-molecule reactions with a given compound constitute the chemical ionization mass spectrum of the compound. The number of ion types in a set of reactant ions is generally small. Because the same reactant ions react with variety of different compounds, the chemical ionization mass spectra produced from the different compounds are comparable with each other and reflect differences in structure and chemical reactivities or quantitative differences in concentration. In this regard, chemical ionization is quite analogous to the other modes of ionization such as electron impact.

A study of the metastable fragmentation of ions produced by 252Cf fission fragment bombardment of bovine insulin

Abstract A time-of-flight mass spectrometric study of the metastable decomposition of ions produced by 252Cf fission fragment bombardment of bovine insulin is presented. The positive secondary ion insulin species investigated include the protonated molecular ion, the doubly charged quasi-molecular ion, the dimer ion, intact A- and B-chain fragment ions, and ions constituting the intense continuum which underlies the discrete peaks. A high proportion of secondary ions which enter the flight tube are observed subsequently to undergo unimolecular fragmentation during flight. Investigation of the temporal distribution of the flight-tube fragmentation indicate that the decays are heavily weighted to favor early times, i.e. high rate constants.

Particle bombardment (keV) mass spectra of ethylene glycol, glycerol, and water at sub-ambient temperatures

Abstract The spectra produced by the title substances when bombarded by a mixed beam of argon atoms and ions with a nominal energy of 8 keV have been obtained at various temperatures ranging downward from ambient temperature. For ethylene glycol and glycerol, the dominant ions in the higher portion of their temperature range were protonated clusters but in the lower portion of the range, the spectra become featureless, consisting of ions at more or less every mass. Similar behavior has been observed previously for methanol. For water, the dominant ions were protonated clusters at −97 and −154°C, i.e. markedly lowering the temperature did not change the spectrum. A quite different spectrum at −54°C was shown to be produced by charge exchange between Ar + and water vapor. Speculation about a possible cause for this behavior is given.

Fission fragment ionization mass spectrometry of polyethers

Abstract The complete fission fragment ionization mass spectra of three polyether oligomer samples have been measured and spectra in the molecular weight region only have been measured for two other samples with known number average molecular weights. The samples consist of methoxypolyethylene glycols with nominal average molecular weights of 750 and 2000 and lauryloxypolyethylene glycol with nominal average molecular weight of 1200. The spectra consist of a series of quasi-molecular ions, four series of ions produced by identified fragmentation processes, and low mass fragment ions produced by unidentified processes. The quasi-molecular ion series are used to obtain average molecular weights for the samples. The agreement between the known number average molecular weights and the corresponding values derived from the mass spectra was excellent. The relative amount of quasi-molecular ions declines with increasing average molecular weight of the polymer sample. More fragmentation is observed with Li + adducts of the polymers than with Na + adducts.