Heroin. II. Preparation, hydrolysis, stability, pharmacokinetics

Heroin is prepared by treating morphine with acetyl chloride or acetic anhydride. It is a simple reaction and the yields are generally quantitative. Nowadays the whole process is illegal. Morphine is the major alkaloid present in the opium poppy. Opium is manufactured illicitly then morphine is extracted from it in clandestine laboratories. Numerous studies were carried out on heroin to investigate its rate of hydrolysis. It has been shown that heroin is rapidly deacylated in aqueous solution at alkaline or acidic pH to form 6-acethylmorphine and finally, to morphine. Heroin also rapidly decomposes in biological medium yielding first 6-acetylmorphine and then morphine. Hydrolysis can be performed in blood and in tissue homogenates. Heroin can be administered by several routes. Smoking and intravenous administration are preferred, but intranasal, intramuscular and subcutaneous administration are also common. Recently, there has been a shift in heroin use patterns from injection to sniffing and smoking. Sharing of the injection equipment can result in several severe infectious diseases, such as AIDS, hepatitis B and C. Soon after administration, heroin metabolizes to 6-acetylmorphine and morphine. Most of the pharmacological activities of heroin are due to these active metabolites. Therefore, knowledge of distribution of 6-acetylmorphine and morphine is essential to understand pharmacological properties of heroin. Heroin, which is relatively nonpolar compound compared with morphine, has high lipid solubility facilitating rapid absorption from the bloodstream and passage through the blood-brain barrier. When heroin is administered by intravenously the drug takes 10 s to reach the brain i.e. pharmacological effects appear quickly.     

Septamycin, a polyether antibiotic. Taxonomy, fermentation, isolation and characterization.

Septamycin is a metal complexing polyether antibiotic produced by a strain of Streptomyces hygroscopicus NRRL 5678. The metabolite, a monocarboxylic acid, was isolated as the sodium salt C48H81NaO16. The crystal structure and absolute configuration were established by X-ray analysis of the p-bromophenacyl derivative. Septamycin has a thirty-carbon backbone and contains seven heterocyclic rings. Supported by direct comparison septamycin proved to be identical with antibiotic A28695 A isolated from Streptomyces albus NRRL 3883. The metabolite is active against gram-positive bacteria and Eimeria tenella (chicken coccidiosis).     

Skin Painting Studies in Mice with 14 Fd&c and D&c Colors: Fd&c Blue no. 1, Red No. 3, and Yellow No. 5, D&C Red No. 7, Red No. 9, Red No. 10, Red No. 19, Red No. 21, Red No. 27, Red No. 31, Red No. 36, Orange No. 5, Orange No. 10, and Orange No. 17

Abstract

A series of 14 cosmetic colors were submitted to dermal toxicity testing in accordance with a protocol designed by the Food and Drug Administration and agreed upon with the Cosmetic, Toiletry and Fragrance Association (formerly the Toilet Goods Association). Dosage levels were based on lipstick use determinations made in a group of human female volunteers. The groups of lipstick colors were divided into three treatment series and painted on twice weekly to an area approximately 6 cm². A total of 1400 mice were used comprising groups of 100 mice (50 per sex) plus additional positive control group of the same size and a vehicle control group of 300 mice (150 per sex). All colors were prepared at 1.0% suspensions in water. The positive control received 3.4–benzpyrene dissolved in acetone. Survival was approximately equivalent in all experimental groups except the positive controls who died earlier consistent with survival recorded by others for 3.4–benzpyrene treated mice. Extramedullary hematopoesis was found in all treated groups, equivalent to the findings in the controls. The repeated application of 0.1 ml containing 1.0% dye did not increase the incidence of neoplasia when compared to controls in any of the groups receiving application of the 14 dyes.     

Capsimycin, a new antibiotic. I. Production, isolation and properties.

Capsimycin is a new antifungal antibiotic produced by a strain of Streptomyces sp. C 49--87. The active substance in the fermented broth was isolated by solvent extraction followed by silica gel column chromatography. The antibiotic melts at 186 degrees C (decomp.) and has a molecular formula C30H40N2O6. It exhibits marked inhibitory activity against Phytophthora capsici (Leaf blight disease of cucumber) and Pythium debaryanum (Damping-off disease of cucumber).     

A new antibiotic, fumaramidmycin. II. Isolation, structure and syntheses.

A new antibiotic fumaramidmycin produced by Streptomyces kurssanovii NR-7GG1 was isolated as colorless crystals. The structure was shown to be N-(phenylacetyl) fumaramide. Starting from fumaramic acid, fumaramidmycin has been synthesized in good yield, in which the key stage involves N-acylated imino ether formation followed by mild acid hydrolysis. Five analogues of fumaramidmycin have also been prepared.     

Antitumor anthracycline antibiotics, aclacinomycin A and analogues. I. Taxonomy, production, isolation and physicochemical properties.

Aclacinomycin A and B, two major components of a new antitumor antibiotic complex, and their 19 analogues were produced by a culture of strain No. MA144-M1, which was identified as Streptomyces galilaeus. They were isolated by chelation with copper ion and silicic acid chromatography, and characterized by physicochemical methods in the anthracycline group of antibiotics.     

Kondensierte Pyrane, 3. Mitt.

Condensed Pyranes, III Pyranopyrimidinecarboxylic esters can be prepared by reacting barbiturates, paraformaldehyde, and the esters of unsaturated carboxylic acids. Three pyranopyrimidinecarboxylic acids obtained by saponification were tested for antiphlogistic activity.     

WS-7338, new endothelin receptor antagonists isolated from Streptomyces sp. No. 7338. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

WS-7338 A, B, C and D, novel endothelin receptor antagonists, have been isolated from fermentation broth of Streptomyces sp. No. 7338. These antagonists were purified from the culture mycelium by extraction with acetone, followed by carbon column chromatography and HPLC. Among them, WS-7338 B showed good activity in an endothelin receptor binding assay with an IC50 of 2.7 x 10(-7) M.     

A new topoisomerase-II inhibitor, BE-10988, produced by a streptomycete. I. Taxonomy, fermentation, isolation and characterization.

A new topoisomerase inhibitor, BE-10988, was isolated from the culture broth of a strain of actinomycetes. The producing strain had a close resemblance to Streptomyces fimicarius and Streptomyces xanthocidicus. The active principle was extracted from the whole broth of strain BA10988 with ethyl acetate and purified by silica gel chromatography and by HPLC. BE-10988 increased DNA-topoisomerase complex formation and inhibited the growth of both doxorubicin-resistant and vincristine-resistant P388 murine leukemia cell lines, as well as sensitive P388 cell lines.     

Sporeamicin A, a new macrolide antibiotic. I. Taxonomy, fermentation, isolation and characterization.

Sporeamicin A, a novel antibiotic, was isolated from the culture filtrate of an actinomycete. The producing organism, strain L53-18, was taxonomically assigned as a species of the genus Saccaropolyspora. The antibiotic was extracted with chloroform and was then purified by crystallization. It was obtained as colorless prisms from ethanolic solutions. Sporeamicin A exhibited a strong UV absorption peak at 276 nm. The molecular formula of sporeamicin A was determined to be C37H63NO12.     

Changes in pharmacy, nursing, and total personnel staffing in U.S. hospitals, 1989-1998.

Pharmacy, nursing, and total hospital personnel inpatient staffing in U.S. medical-surgical hospitals for 1989, 1992, 1995, and 1998 was studied. Nursing and total personnel staffing data were obtained from the American Hospital Association, and pharmacy personnel data were obtained from the National Clinical Pharmacy Services database. Between 1989 and 1998, mean +/- S.D. registered-nurse staffing per 100 occupied beds increased from 124.46 +/- 92.24 to 196.57 +/- 131.92, or 57.94%. Pharmacist staffing per 100 occupied beds increased from 6.47 +/- 3.01 to 7.95 +/- 4.88, or 22.87%. The total number of registered nurses increased by 126,960 (15.78%), and the total number of pharmacists declined by 320 (0.72%). The increase in pharmacist staffing per 100 occupied beds was due almost entirely to decreases in hospital census between 1989 and 1998. Total hospital personnel staffing per 100 occupied beds and the absolute number of hospital employees increased at much higher rates (55.2% and 12.95%, respectively) than pharmacist staffing. Pharmacy technician staffing per 100 occupied beds increased by 42.96%, and pharmacy clerk staffing increased by 25.37%. Between 1989 and 1998, pharmacist staffing in U.S. medical-surgical hospitals increased at less than half the rates for registered nurses and total hospital personnel.     

Thrazarine, a new antitumor antibiotic. I. Taxonomy, fermentation, isolation and biological properties

Thrazarine, O-[(3R)-2-diazo-3-hydroxybutyryl)]-L-serine, is a new antitumor antibiotic produced by Streptomyces coerulescens MH802-fF5. Thrazarine was isolated from culture filtrate by Sephadex LH-20 column chromatography and reversed phase HPLC. Thrazarine induced cytolysis of tumor cell lines co-cultured with nonactivated macrophages. This effect was tumor specific because the nontumorigenic cells were not lysed by macrophages in the presence of thrazarine. Thrazarine inhibited DNA synthesis and growth of tumor cells directly. It showed neither antimicrobial activity nor the inhibition of transamidation reactions in contrast to azaserine. Toxicities of thrazarine were much weaker than those of azaserine.     

Reveromycins, new inhibitors of eukaryotic cell growth. I. Producing organism, fermentation, isolation and physico-chemical properties.

New antibiotics named reveromycins A, B, C and D were isolated as inhibitors of mitogenic activity induced by epidermal growth factor (EGF) in a mouse epidermal keratinocyte. Reveromycins were produced by a soil actinomycete (strain SN-593) which belongs to the genus Streptomyces.     

Direct automated EMIT d.a.u. analysis of N,N-dimethylformamide-modified serum, plasma, and postmortem blood for benzodiazepines, benzoylecgonine, cannabinoids, and opiates

Serum, plasma, and postmortem blood treated with two volumes of N,N-dimethylformamide (DMF) and centrifuged, were directly analyzable by means of the EMIT d.a.u. reagents on the Syva Autocarousel in the same manner as urine. Cutoff values in milligrams (immunochemically cross-reactive analyte equivalents)/L are 0.05 for morphine (MOR), 0.15 for benzoylecgonine (BZE), 0.20 for oxazepam (OX), and 0.02 for 11-nor-delta 9-tetrahydrocannabinol carboxylic acid (THCC). The relationship of concentrations (micrograms/mL serum) to absorbance changes (delta A) were S-shaped up to greater than 3.0 for MOR, 4.0 for BZE, greater than 5.0 for OX, and 0.2 for THCC. Beyond these maximal concentrations, delta A values declined. Thus, negatives should be repeated on substantially diluted aliquots to avoid missing extraordinarily high positives. "False" quantitative negative/positive noncongruence between total EMIT cross-reactives and free-drug analyses by gas chromatography/mass spectrometry (GC/MS) were 0/17 (N = 75) for opiates, 8/0 (N = 119) for cocaine products, and 19/5 (N = 103) for cannabinoids. For benzodiazepines (N = 58) the "false" negative/"false" positive ratio of EMIT (total)/high performance liquid chromatography (HPLC) (free) was 4/4. Within-day precision as coefficient of variation (CV) of quantitative estimates was 8-18%. For between-day precision, quantitative estimates varied by 8% for MOR, 15% for BZE, 18% for OX, and 34% for THCC.     

Book Review of Alcohol: No Ordinary Commodity. Research and Public Policy T. Babor,R. Caetano,S. Casswell,G. Edwards,N. Giesbrecht,K. Graham,J. Grube,P. Grunewald,L. Hill,H. Holder,R. Homel,E. Osterberg,J. Rehm,R. Room and I. Rossow. Oxford: Oxford University Press, 2003, 301 pp., £29.50 (pbk). ISBN 0 19 263261 2.

The results of the first 9 months of the implementation of a three-stage treatment programme for alcohol dependence are presented. Preparation groups (PGs) can be the main treatment option during this stage of the programme for almost all clients and Relapse Prevention groups, immediately after detoxification, for up to 75% of clients. Those participating in the PGs are doing significantly better as far as detoxification completion, 1 and 3 months post detoxification abstinence is concerned.     

Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. I. Taxonomy, fermentation, isolation and biological activity.

A novel class of macrolides for which the name sanglifehrins is proposed, has been discovered from actinomycete strains based on their high affinity binding for cyclophilin A (CypA), an immunophilin originally identified as a cytosolic protein binding cyclosporin A (CsA). The sanglifehrins were produced by Streptomyces sp. A92-308110. They were isolated and purified by extraction and several chromatographic, activity-guided steps. Sanglifehrins A and B exhibit a 10 to approximately 20 fold higher affinity for CypA than CsA, whereas the affinity of sanglifehrins C and D for CypA is comparable to that of CsA. Sanglifehrins exhibit a lower immunosuppressive activity than CsA when tested in the mixed lymphocyte reaction. Their in vitro activity indicates that they belong to a novel class of immunosuppressants.     

Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. II. Structure elucidation, stereochemistry and physico-chemical properties.

A novel class of macrolides, the sanglifehrins, was discovered by screening of actinomycete strains with a cyclophilin-binding assay. The chemical structures and absolute stereochemistries of the sanglifehrins A, B, C and D were determined unambiguously by NMR-techniques and by X-ray crystallography of the complex with cyclophilin A. Sanglifehrin A consists of a 22-membered macrocycle containing a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent. Sanglifehrins A and B are genuine metabolites whereas sanglifehrins C and D are artefacts.     

Argifin, a new chitinase inhibitor, produced by Gliocladium sp. FTD-0668. II. Isolation, physico-chemical properties, and structure elucidation

A new chitinase inhibitor, named argifin, was isolated from the cultured broth of a fungal strain Gliocladium sp. FTD-0668. Argifin was purified from the cultured mycelium by the combination of cation exchange, anion exchange, adsorption, and gel filtration chromatographic methods. The structure of argifin was elucidated as cyclo(N(omega)-(N-methylcarbamoyl)-L-arginyl-N-methyl-L-phenylalan yl-beta-L-aspartyl-beta-L-aspartyl-D-alanyl) by NMR experiments and other spectroscopic analyses.     

Vitaminology for practitioners. II. Avitaminoses, risk, latency period, classification

The concept of risk in the field of avitaminoses is very important and useful for the practitioner, who should consider two aspects: a) risk factors, which could be individual (physiological, pathological and psychological) and extra-individual (alimentary, environmental, etc.); b) subjects with an elevated risk of avitaminosis (childhood, old age, pregnancy, etc.). In these subjects the risk can be a generical one, when there is an elevated requirement for all vitamins (nursing women, sportmen, etc.) or a specific one, when there is a high requirement only for a single vitamin (osteomalacia, some professional diseases, use of oral contraceptives) or a vew of them (alcoholism, diabetes, etc.). On the basis of this kind of knowledge it is easy for the practitioner to estimate which vitamins are necessary for each subject or for a group of subjects in physiological or in pathological conditions. For example, there is an elevated risk of apyridoxinosis in old age (acalciferolosis in aged women), of athiaminosis and apyridoxinosis in diabetes, of apyridoxinosis in oral contraceptives users, of axeroftolosis in hyperthyroidism, of athiaminosis, apyridoxinosis, aniacinosis and anascorbosis in alcoholics. In the second chapter the concept of the latency period in avitaminosis is illustrated. This period corresponds to the interval between the moment when deficiency stimulus starts operating and the moment when its effect, that is the picture of avitaminosis, appears. The latency time is not measurable, on account of the difficulties in establishing the onset of the deficiency stimulus; generally it is very long and is followed by the period of biochemical symptomatology and subsequently by the one of clinical symptomatology. Each of these three phases can be further divided in several steps, which have summarized in a Table. The last chapter is dedicated to the classification of avitaminoses. From the etiopathogenetic point of view avitaminoses can be due to: a) deficiency of introduction (alimentary level)); b) deficiency of absorption (enteric level); c) deficiency of utilization (tissue level). From the clinical point of view avitaminoses can be distinguished in deficiency with: a) a complete clinical symptomatology (scurvy, beriberi, pellagra, rickets, osteomalacia, xerophthalmia, hemeralopia); b) an incomplete clinical symptomatology (mono- or oligo-symptomatic or partial clinical picture); c) a biochemical symptomatology only (subclinic or clinically asymptomatic picture).     

Primary socialization theory. Developmental stages, spirituality, government institutions, sensation seeking, and theoretical implications. V.

This fifth and final paper in the series on primary socialization theory includes discussion of issues raised by participants in a forum on the theory. The theory states that drug use and deviant behaviors occur as an outcome of bonding with primary socialization sources and the transmission of norms through those sources. Personal traits and secondary socialization sources influence drug use and deviance indirectly and through their effects on the primary socialization process. Developmentally, the only primary socialization source for the preschool child is the family. In early grade school years, the primary socialization sources are the family and school. Peer clusters emerge as a primary socialization source later, with their greatest effect occurring during adolescence. Adults have varied primary socialization patterns. Levels of ego development among adults may alter the primary socialization process. Spirituality is defined, and its influence on drug use is discussed. Government institutions, such as the criminal justice system, welfare, and child protective services, are now included among secondary socialization sources. The fact that the general theory of primary socialization is not ethnocentric or temporocentric is discussed. Implications of the theory for understanding existing or potential risk and protective factors for deviance, and for improving the effectiveness of prevention and treatment are discussed. [Translations are provided in the International Abstracts Section of this issue.]