Preparation and configuration of racemic and optically active analgesic dialkylaminoalkylnaphthalenes.

The alkylaminoalkylnaphthalene 3 shows interesting opioid-like analgesic properties, mu-selective ligand competition, and enkephalin hydrolyzing enzyme inhibition. 3 possesses two chiral centers and can exist as two racemic pairs and four diastereomers. Since the binding of opioids with the receptor is stereoselective, it was important to have the two racemic pairs as well as the four diastereomers. In this paper the synthesis of the (1R,2R/1S,2S)- and (1R,2S/1S,2R)-racemates and the (1R,2R)- and (1S,2S)-enantiomers of the 1-ethyl-1-hydroxy-1-[2-(6-hydroxynaphthyl)]-2-methyl-3- dimethylaminopropane 3 is considered and the determination of absolute configuration is described. The (1R,2R/1S,2S)-3 and (1R,2S/1S,2R)-3 racemates and the (1R,2R)-3 and (1S,2S)-3 enantiomers were prepared by reaction of the racemic and optically active 1-dimethylamino-2-methylpentan-3-one 2, respectively, with the lithiation product obtained from 2-bromo-6-tetrahydropyranyloxynaphthalene and acidic hydrolysis. The optical resolution of aminoketone 2 was carried out via fractional crystallization of salts (+)- and (-)-dibenzoyltartrates. The configuration of the optically active compounds was determined by X-ray analysis of a crystal of (+)-(1R,2R)-3.HCl.H2O. Preliminary pharmacological tests showed that (+)-(1R,2R)-3 enantiomer is able to induce opioid-like analgesia with a relative potency 2.5 times that of (1R,2R/1S,2S)-3 and about 4 times that of morphine.

Role of the oligosaccharide inner core in the inhibition of human leukocyte elastase by chondroitin sulfates.

A chondroitin 4-sulfate and 6-sulfate mixture (CS) extracted from selachian cartilage and a purified preparation of the above glycosaminoglycans from bovine trachea, have been comparatively assayed with respect to the kinetics of human elastase activity. The selachian extract CS, but not the bovine one, inhibited the hydrolysis of N-tert-butyloxycarbonyl p-nitrophenyl ester in vitro (ki = 4.0 micrograms/ml). By fractioning both extracts on Sephadex, the inhibition was found to be related to the presence of a 40-50 KD peak (ki = 2.3 micrograms/ml). This particular fraction was present in the selachian extract CS from matrix, being absent from the bovine trachea extract CS (70% CSC) from Sigma. It showed a single Coomassie- and PAS-stained band approximately 47 kDa in m.w. on sodium dodecylsulfate polyacrylamide gel electrophoresis. Cleavage of the O-glycoside link by alkali hydrolysis of the eluted band, did not influence the enzyme inhibition (ki = 2.1 micrograms/ml). At variance, extensive hydrolysis of ester linkages by fluoride ion resulted in the lowering of inhibition (ki = 5.8 micrograms/ml). Apparently, the preservation of the trisaccharide region in the carbohydrate residues of proteoglycan is mandatory for the inhibition of elastase by low-sulfated chondroitinsulfates.

Glycosaminoglycan chondroprotection: pharmacological vistas.

Chondroprotection is a somewhat new field in the therapy of osteoarthritis, which is designed to improve cartilage repair as well as enhance joint remodeling. It clearly results from both laboratory models as well as from studies on human osteoarthritis, that cartilage contains biological resources to meet the repair of degenerative injuries and inflammation. Interestingly, sulfated glycosaminoglycans from matrix inhibit leukocyte protease and complement-mediated immunological reactions. By fractioning cartilage glycosaminoglycans from Selachus (Matrix), evidence has been obtained that a proper chondroitinsulfate sequence, which is able to inhibit elastase, may be released from cartilage proteoglycans by cleavage of the xyl-ser O-glycosidic bond. Since a number of sulfated glycosaminoglycans have a regulatory function in an array of tissues, attention is drawn to possible regulatory properties of selected sequences of matrix chondroitinsulfate, as far as chondroprotection is concerned.

Complement in vitro inhibition by a low-sulfate chondroitin sulfate (matrix).

In this study, the ability of low-sulfate chondroitin sulfate (Matrix), a glycosaminoglycan that does not exhibit anticoagulant action, to inhibit the activation of complement has been evaluated. Two different in vitro tests were employed: lysis of mouse splenocytes sensitized with monoclonal antibodies and lysis of red blood cells sensitized using a rabbit antiserum towards those cells. In both tests, lyophilized rabbit complement was used as complement source. The low-sulfate chondroitin sulfate Matrix has been compared with a hypersulfated one (Arteparon). Both compounds share anticomplementary activity in vitro although potency appears to be related to the sulfate content of the chondroitin.

A pharmacological approach to glycosaminoglycans.

A pharmacological approach to glycosaminoglycans (GAG) is presented, reviewing their synthesis, functions and in particular their mechanism as drugs. The application of GAG sulfates in osteoarthritis therapy is examined in detail.

Illicit use of methadone in heroin addicts in Rome.

Although in several countries heroin addicts have been found to engage in illicit use of methadone, no studies have been addressed to this behavior in Italy. The present study gives evidence that methadone dispensed by public health services in Rome is paralleled by a black market in this drug. Of sixty-five heroin addicts hospitalized for medical or surgical problems, the majority (89.2%) referred to the existence of an illicit methadone market in Rome, and 38% used it. When asked why they bought illicit methadone the addicts stated that the daily dose obtainable from public health services was inadequate. However this statement is in contrast with the evidence that the heroin addicts using illicit methadone had highest daily doses similar to those of heroin addicts not referring to the illicit methadone market. We wonder whether illicit use of methadone is influenced by the therapeutic benefit that addicts expect to obtain from methadone. These "expectations" may lead heroin addicts to extend consumption of methadone to alleviate problems altogether unrelated to the withdrawal syndrome. If so, the illicit market in methadone may be sustained not by the drug's addictive properties but by its therapeutic effects.

Seroprevalence of anti-Chlamydia trachomatis IgG in outpatients attending a sexually transmitted disease clinic in Italy.

Prevalence of anti-Chlamydia trachomatis specific IgG antibodies was evaluated in a sexually transmitted disease outpatient population composed of 741 heterosexuals, 470 males and 271 females, and of 147 homosexual-bisexual men. The prevalence rates were 60.0% in heterosexual males, 50.6% in females and 73.5% in homosexuals-bisexuals. A positive association between age and antibody prevalence was found in males. Among heterosexuals there is an increasing trend of seropositivity with number of partners during the previous year. A significant association between anti-chlamydial and anti-herpes simplex, type 2, antibodies has been demonstrated.

[Oculogenital infections caused by Chlamydia trachomatis]. / Infezioni oculogenitali da Chlamydia trachomatis.

C. trachomatis, the causative agent of hyperendemic trachoma and lymphogranuloma venereum, is also responsible of sexually transmitted infections. It is now recognized that genital chlamydial infections are the major cause of sexually transmitted diseases in Western industrialized countries, surpassing the importance of gonococcal infections. C. trachomatis, obligate intracellular parasite, enters the epithelial cells of genital mucosae and can reach, luminally, other organs of both female and male genital tract originating different clinical pictures. Vertical transmission of the microorganism from the infected mother to the newborn is of great importance. The infection takes place during delivery and can lead to disease in the newborn such as inclusion conjunctivitis and interstitial pneumonia. The present review deals mainly with clinical features and the most frequent complications of chlamydial infections. The identification of subjects at risk and the improvement of diagnostic techniques is of utmost importance since a prompt antibiotic treatment can eradicate the microorganism at least in uncomplicated infections, preventing the sequelae of the disease.

Khat chewing spread to the Somali community in Rome.

The habit of chewing Khat (Catha edulis) to experience its euphorizing and psychostimulant effects has prevailed for centuries among the inhabitants of the Horn of Africa and the Arabian peninsula. In recent years, air transport has removed the major obstacle to the diffusion of Khat, its perishableness. Khat is now air-freighted to Europe and we were able to buy some in Rome. We report the results of interviews with 20 members of the Somali community in Rome, who had continued their habit of chewing Khat whilst abroad. They asserted that they gathered together whenever possible, but preferably at weekends, to chew moderate quantities of Khat (one bundle, about 400 g). The customary habit of drinking tea or other soft drinks containing methylxantines during Khat sessions was maintained and very few subjects admitted drinking alcohol. In this small study sample, Khat chewing still seems to be a social event, as it is in Somalia.

Indirect immunofluorescence application in the epidemiological study of hepatitis A.

We used IIF test for seroepidemiological study on 531 sera divided in age-groups obtained from apparently healthy subjects of Rome. Our results confirm the endemicity of HAV (Hepatitis A virus) infection in Rome with a prevalence of more than 50%. The application of the anti-HAV IIF (Indirect Immunofluorescence) test to a large number of sera demonstrated its usefulness as a quantitative and qualitative test in the epidemiological field.

Clinical and experimental evidence of an opiate-like activity of lefetamine.

A case of lefetamine abuse (0.9-1.8 g/day in 15-30 i.m. divided doses) is reported. In this patient, the administration of naloxone precipitated a mild opiate-like withdrawal syndrome, characterized by mydriasis, piloerection, yawning and a slight increase of blood pressure. The complete withdrawal of lefetamine, substituted by a placebo regimen, aggravated these symptoms. Furthermore, experimental results showed that lefetamine induced a naloxone-reversible inhibition of the guinea-pig ileum contractile response to electric field stimulation, and that naloxone pretreatment of mice prevented lefetamine antinociceptive activity in the hot-plate test. The clinical and experimental findings suggest that lefetamine has an opiate-like activity.

Prolonged analgesia induced by cathinone. The role of stress and opioid and nonopioid mechanisms.

Cathinone, the active principle of Catha edulis (khat), shows long-lasting analgesic effects when the tail-flick test is used in rats. The involvement of monoamines, endogenous opioids and stress in this analgesic effect was tested. Both early (30 min) and late (24 h) analgesic effects of cathinone were prevented by reserpine or p-chlorophenylalanine, which deplete catecholamines or serotonin, respectively, and by nomifensine, which prevents neuronal uptake of biogenic amines and amphetamines. The same inhibitory effect was obtained with a high dose (4 mg/kg) of naloxone. However, rats made tolerant to morphine retained both early and late analgesic response to cathinone. The increase in plasma ACTH induced by the tail-flick test at 30 min and 24 h was significantly enhanced by cathinone, in a naloxone-reversible way. However, the analgesic responses shown at these times were not prevented by either dexamethasone or adrenalectomy. We conclude that the prolonged analgesia induced by cathinone is primarily due to an amphetamine-like activation of monoaminergic pathways, but requires the integrity of non-mu-opioid mechanisms. The involvement of the adrenohypophyseal axis in this cathinone effect is less probable.

Lipolytic and enkephalinase inhibitory activities of polypeptides from placental autolysate prepared for therapeutic purposes.

In order to study the pharmacodynamic basis of therapeutic uses of placental extracts researches was carried out on Sephadex G25 factors of autolytic extract of human placenta. Four of these fractions showed immunoreactivity for both beta-endorphin and ACTH, and were able to stimulate lipolysis in rabbit adipose tissue. An inhibition of the enkephalinase activity of rat brain homogenates was displayed by placental fractions of low molecular weight. These results suggest that beta-endorphin and ACTH play a roles in the pharmacological activity of placental extracts.