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Biomedical subjects

A Mattioli

Publications and source records attributed to A Mattioli.

At least 19 recordsLinked to original sources
PubMed1999

Inhibition of [3H]thymidine incorporation into DNA of rat regenerating liver by 2',2'-difluorodeoxycytidine coupled to lactosaminated poly-L-lysine.

The expression of asialoglycoprotein receptor (ASGP-R) on human hepatocarcinoma cells might be exploited to reduce the extrahepatic toxicity of DNA synthesis inhibitors by their conjugation with galactosyl- terminating peptides. We conjugated 2',2'-difluorodeoxycytidine (dFdC), an inhibitor of DNA synthesis active on solid tumors, with lactosaminated poly-L-lysine (L-poly(LYS)). In experiments in vitro, L-poly(LYS)-dFdC inhibited proliferation of Hep G2 cells, a human hepatocarcinoma cell line which maintains the ASGP-R. Inhibition was rescued by asialofetuin. To study the pharmacological action of the conjugate in vivo, we used rats 18-24 hr after 2/3 hepatectomy and observed that regenerating hepatocytes expressed ASGP-R on their surface and internalized L-poly(LYS)-dFdC. Conjugate uptake by bone marrow, spleen, and intestine was negligible. We also found that L-poly(LYS)-dFdC inhibited [3H]thymidine incorporation into DNA of regenerating liver. These results indicated that hepatectomized rats were a suitable animal model to study the pharmacological action, on DNA-synthesizing hepatocytes, of conjugates binding to ASGP-R and carrying inhibitors of DNA synthesis. L-poly(LYS)-dFdC also inhibited [3H]thymidine incorporation in bone marrow, spleen, and intestine. Evidence was obtained that inhibition of DNA synthesis in extrahepatic tissues was a consequence of drug release from hepatocytes into blood-stream after the bond with the carrier has been broken down within liver cells. Possible ways of reducing the exit of dFdC from liver cells, thereby obtaining an inhibition of DNA synthesis restricted to dividing hepatocytes, were discussed.

Amino Sugars↗
PubMed1999

The exercise pressor reflex and changes in radial arterial pressure and heart rate during walking in patients with arteriosclerosis obliterans.

Little is known about the time course and extent of the changes in radial arterial pressure and heart rate taking place in patients with arteriosclerosis obliterans during walking, as well their subtending mechanisms. For this reason the authors measured these variables in 23 patients with arteriosclerosis obliterans and in nine normal subjects (control group), during treadmill walking and several tests. In the patients a rapid and marked increase in radial arterial pressure was recorded during walking, whereas the same parameter either fell abruptly or persisted at elevated levels during recovery. This pattern markedly differed from that recorded in normal subjects, and it was mainly brought about by the activation of the exercise pressor reflex. The following findings suggested that the exercise pressor reflex was activated: the conditions required for activation of the reflex were present in our patients; the pressure changes observed during walking tightly paralleled the changes due to this reflex activation; the hypertensive response to walking was enhanced by increases in severity of disease and in walking speed and duration; the reflex activity persisted during recovery; and the pressure pattern during walking was reproduced by walking with arrested blood circulation to a lower limb. On the contrary, the behavior of heart rate was similar in patients and normal subjects both during walking and recovery because it was not influenced by the exercise pressor reflex.

Adult↗
PubMed1997

Ribavirin conjugated with lactosaminated poly-L-lysine: selective delivery to the liver and increased antiviral activity in mice with viral hepatitis.

Ribavirin (RIBV) is a useful drug in the treatment of chronic type C hepatitis but displays a toxicity for red blood cells (RBC), which limits its dosage and necessitates withdrawal in some patients. Selective concentration of RIBV in liver should improve therapeutic results. Liver targeting can be achieved by coupling the drug to galactosyl-terminating peptides, which specifically enter hepatocytes. In the present work, we conjugated RIBV to lactosaminated poly-L-lysine (L-Poly(Lys)), a hepatotropic carrier enabling intramuscular (IM) administration of conjugates. The L-Poly(Lys)-RIBV conjugate had a heavy drug load (312-327 microg of RIBV in 1 mg of conjugate) and was very soluble in 0.9% NaCl (200 mg/mL). The conjugate was devoid of acute toxicity in mouse. When incubated with human or mouse blood, it did not release the drug. After IM administration to mice, the conjugate was selectively taken up by the liver, where the drug was released in a pharmacologically active form. This was demonstrated using mice infected with a strain of murine hepatitis virus (MHV) sensitive to RIBV. Coupled RIBV, IM injected, inhibited MHV replication in liver at a daily dose two to three times lower than that of the free drug. In mice IM injected with a conjugate tritiated in the RIBV moiety, the ratios between the levels of radioactivity in liver and RBC were two times higher than in animals injected with free tritiated RIBV. In conclusion, the present results support the possibility that the chemotherapeutic index of RIBV in chronic type C hepatitis can be increased by conjugation with L-Poly(Lys).

Amino Sugars↗
PubMed1997

Hepatotropic conjugate of adenine arabinoside monophosphate with lactosaminated poly-L-lysine. Synthesis of the carrier and pharmacological properties of the conjugate.

BACKGROUND/AIMS: The hepatotropic conjugate of adenine arabinoside monophosphate with lactosaminated poly-L-lysine (L-Poly(Lys)) must have a high solubility in order to be injected in a small volume compatible with the intramuscular route. In this paper the molecular weights of Poly(Lys) which allowed the synthesis of conjugates with the properties of high solubility and limited loss by the kidney were determined and a procedure for obtaining Poly(Lys) preparations with the required range of polymerization has been described. METHODS: Conjugates were prepared using Poly(Lys) of different molecular weights obtained by the procedure described here or purchased from a commercial source. Their solubility and renal loss in mice was determined. RESULTS: Poly(Lys) with molecular weights ranging from 45,000 and 65,000 Da guarantees high solubility and low renal elimination of the conjugates. Conjugate preparations with these properties, intramuscularly administered to woodchuck hepatitis virus-infected woodchucks for 37 days at a daily dose of 5.8 mg/kg exerted a strong antiviral activity. These preparations were devoid of acute toxicity in rat and caused no toxic effects when injected intramuscularly daily for 28 days at a dose ten times higher than that active in woodchucks. CONCLUSIONS: The results support the possibility of a clinical use of L-Poly(Lys) to obtain liver targeting of adenine arabinoside monophosphate for the treatment of chronic hepatitis B virus infection.

Amino Sugars↗
PubMed1997

Liver targeting of antiviral nucleoside analogues through the asialoglycoprotein receptor.

In order to reduce the extrahepatic side-effects of antiviral nucleoside analogues in the treatment of chronic viral hepatitis, these drugs are conjugated with galactosyl-terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor present in large amounts and high affinity only on these cells. Within hepatocytes the conjugates are delivered to lysosomes where enzymes split the bond between the carrier and the drug, allowing the latter to become concentrated in the liver. The validity of this chemotherapeutic strategy has been endorsed by a clinical study. Adenine arabinoside monophosphate (ara-AMP), conjugated with lactosaminated human serum albumin (L-HSA) and administered to hepatitis B virus (HBV)-infected patients for 28 days, exerted an antiviral activity to the same extent as the free drug without producing any clinical side-effects, including the severe neurotoxicity caused by the free drug. Preclinical studies are now underway with conjugates obtained using lactosaminated poly-L-lysine (Lac-poly(Lys)) as the hepatotropic carrier. These new conjugates have some advantages over those prepared with L-HSA: they can be administered by the intramuscular route; they are obtained entirely by chemical synthesis, thus eliminating the problems involved in the use of haemoderivatives; they have a heavy drug load, which permits administration of smaller quantities of conjugate that are more easily digested in lysosomes; and they enable higher quantities of drug to be introduced into hepatocytes. The results of the experiments with two Lac-poly(Lys) conjugates, one with ara-AMP and one with ribavirin, are reported in this review.

Animals↗
PubMed1997

Hemodynamic changes in the lower limbs during treadmill walking in normal subjects and in patients with arteriosclerosis obliterans.

The effects of arteriosclerosis obliterans on the hemodynamic changes that occur during walking are largely unknown. For this reason, the authors measured blood pressure by transducer from the posterior tibial artery and vein at both ankles in 23 patients with arteriosclerosis obliterans of different severity and at the left ankle in 8 normal subjects. Radial artery pressure was also measured, and the differences between mean radial and ankle arterial pressures (pressure gradient) and between mean arterial and venous ankle pressures (foot perfusion pressure) were calculated. All measurements were made simultaneously and continuously during standing, treadmill walking at five different speeds, and during recovery. Compared with the normal subjects, the patients exhibited a greater pressure gradient and lower ankle arterial pressure and foot perfusion pressure at rest. During walking and recovery these intergroup hemodynamic differences were markedly enhanced, and ankle venous pressure was lower in the patients than in the normal subjects. In the patients the hemodynamic pattern depended on disease severity at rest and on both disease severity and walking speed during walking and recovery.

Adult↗
PubMed1997

[Factors involved in gingival hyperplasia caused by diphenyl hydantoin].

BACKGROUND: The objective of this clinical study is to evaluate the relationship between the degree of the phenytoin-induced gingival overgrowth (GO) and factors like bacterial plaque, the "individual predisposition" to develop GO and multiple drug based therapy. MATERIALS AND METHODS: During a one year period we examined 20 epileptic patients taking phenytoin alone or in association with other drugs; they underwent initial therapy and in some cases periodontal surgery. RESULTS: The long-term control showed that a better oral hygiene and an association of drugs may reduce the gingival overgrowth but not eliminate it. CONCLUSION: A determining factor in developing GO seems to be the "individual predisposition" probably due to the presence of a fibroblast subpopulation sensitive to phenytoin.

Gingival Hyperplasia↗
PubMed1996

Adenine arabinoside monophosphate coupled to lactosaminated human albumin administered for 4 weeks in patients with chronic type B hepatitis decreased viremia without producing significant side effects.

A conjugate of adenine arabinoside monophosphate (ara-AMP) with the liver-targeting molecule lactosaminated human serum albumin (L-HSA) was administered by intravenous infusion for 28 days to eight patients with chronic type B hepatitis. The daily dose varied among the patients, ranging from 34 mg/kg to 53 mg/kg (equal to 1.5 and 2.3 mg/kg ara-AMP, respectively). Pharmacokinetic analysis indicated that, at every dose tested, the conjugate was disposed of without accumulation. Viral DNA serum levels fell markedly during treatment; values rose again when treatment was ceased. The L-HSA-ara-AMP conjugate did not cause either the neurotoxic side effects of free ara-AMP or other adverse clinical reactions. It produced a significant increase both in serum alkaline phosphatase activity and platelet number, and a small but significant decrease in erythrocyte number. These laboratory parameters returned to normal levels within 2 months after treatment. The conjugate induced the production of small amounts of antibodies (approximately 20 pmol of conjugate bound by 1 mL of serum) in one patient only. In conclusion, the present results indicate that the L-HSA-ara-AMP conjugate can exert the antiviral activity of ara-AMP in chronic type B hepatitis patients without producing the neurotoxic side effects which hamper a 4-week period of treatment with the free drug.

Adult↗
PubMed1995

Selective delivery to the liver of antiviral nucleoside analogs coupled to a high molecular mass lactosaminated poly-L-lysine and administered to mice by intramuscular route.

In order to obtain hepatotropic conjugates of antiviral drugs suitable for intramuscular administration, three nucleoside analogs (adenine arabinoside monophosphate, ribavirin and azidothymidine) were coupled to a high molecular mass lactosaminated poly-L-lysine. The conjugates had a high molar ratio drug/conjugate and after intramuscular administration to mice, were selectively taken up by the liver and eliminated by the kidney only in minute quantities. The high molar ratio and low renal elimination are important properties not possessed by conjugates previously prepared by using a small molecular mass lactosaminated poly-L-lysine. The conjugate with adenine arabinoside monophosphate (ara-AMP) was found to be devoid of acute toxicity for mice and in spite of its high molecular dimension (Mn = ca. 72,500) did not induce antibodies in this animal after repeated intramuscular injections. This conjugate could have two advantages over a similar complex of ara-AMP with lactosaminated human albumin currently under clinical trials for the treatment of chronic type B hepatitis which must be injected intravenously: it might provide better patient compliance since it is injectable intramuscularly and could introduce larger amounts of ara-AMP into hepatocytes due to its higher drug/carrier molar ratio.

Amino Sugars↗
PubMed1995

Inhibition of woodchuck hepatitis virus replication by adenine arabinoside monophosphate coupled to lactosaminated poly-L-lysine and administered by intramuscular route.

We prepared a hepatotropic conjugate, suitable for intramuscular (IM) injection, of lactosaminated poly-L-lysine with adenine arabinoside monophosphate (ara-AMP), a drug active against hepatitis B virus (HBV). We studied its organ distribution in mice and its antiviral activity in woodchucks that are carriers of woodchuck hepatitis virus (WHV). In mice, after IM administration of a conjugate tritiated in the drug moiety (5.2 micrograms/g equal to 2 micrograms/g of ara-AMP) radioactivity in liver was three times greater than in kidney, spleen, and intestine. On the contrary, after IM injection of unconjugated, tritiated, ara-AMP (5 micrograms/g) the amounts of radioactivity in liver, spleen, and kidney were similar. Unconjugated ara-AMP and the conjugate were administered IM to woodchucks for 13 days. Unconjugated ara-AMP decreased viremia at the daily dose of 5 mg/kg but was ineffective at 2.5 mg/kg. The conjugate at the daily doses of 4.2 and 7 mg/kg (equal to 1.5 and 2.5 mg/kg of ara-AMP, respectively) markedly lowered the viremia, which decreased to undetectable levels in the animals treated with the higher dose. Assuming that in HBV-infected patients the same doses will be active, then the amount of conjugate (soluble at 200 mg/mL) required by a 70-kg patient will be contained in a volume of 1.5 to 2.5 mL, compatible with the IM route. Compared with a similar ara-AMP complex with lactosaminated human albumin, currently being studied in clinical trials for the treatment of chronic type B hepatitis, which must be infused intravenously, the present conjugate might provide more patient compliance because of IM administration.

Amino Sugars↗
PubMed1995

Liver targeting of adenine arabinoside monophosphate (ara-AMP) by coupling to lactosaminated human serum albumin.

Adenine arabinoside monophosphate (ara-AMP) is a potent antiviral agent against hepadnaviruses but its use in the treatment of chronic hepatitis B is hampered by severe neurotoxic side effects, which are dose dependent. In order to reduce these adverse reactions and to adopt the lysosomotropic approach to antiviral chemotherapy, ara-AMP was coupled to lactosaminated human serum albumin (L-HSA), a neoglycoprotein which specifically penetrates hepatocytes. In mice with Ectromelia virus hepatitis, ara-AMP coupled with L-HSA was selectively delivered to liver cells in which it was released in a pharmacologically active form. Moreover in woodchucks with WHV hepatitis and in patients with chronic HBV infection, coupled ara-AMP inhibited hepadnavirus replication at a dose (1.5 mg/kg/day) 3-6 times lower than the free drug. A clinical study using a 28-day period of treatment with conjugated ara-AMP at 1.5 mg/kg/day has now been started. In the first 6 patients the treatment has been completed. The conjugate inhibited virus growth without producing any side effects. L-HSA-ara-AMP conjugate must be given by intravenous infusion. New hepatotropic conjugates of ara-AMP have been recently prepared which could be administered by bolus intravenous injection or by intramuscular route. These complexes might assure a better compliance in patients with hepatitis B virus infection for a long lasting liver targeted antiviral treatment.

Amino Sugars↗
PubMed1995

[Surgery of abdominal aortic aneurysm and concomitant disease of the digestive tract].

The incidence of intra-abdominal diseases associated with abdominal aortic aneurysm is increasing, and it is difficult to decide whether to operate the abdominal disease first, the aneurysm first or both simultaneously. Variables used in decision analysis include type, stage and life expectancy of the cancer, rupture rate of abdominal aortic aneurysm. Symptomatic lesion should be treated first. Absolute indication for operation initially on the aneurysm is the presence of symptoms of rupture. Aortic abdominal aneurysmectomy combined with surgical removal of an intestinal disease may present severe risks as infection of the graft and anastomotic leakage, especially during lower abdominal surgery. In this paper authors present four cases of AAA which had intra-abdominal surgical disease. They were treated by one-stage operation with no complications. Criteria to assess timing of surgical treatment of abdominal surgical diseases concomitant to AAA are discussed.

Aged↗
PubMed1994

A conjugate of lactosaminated poly-L-lysine with adenine arabinoside monophosphate, administered to mice by intramuscular route, accomplishes a selective delivery of the drug to the liver.

A conjugate of the antiviral agent adenine arabinoside monophosphate (ara-AMP) with a low molecular mass lactosaminated poly-L-lysine, administered to mice by i.m. route, selectively delivers the drug to the liver. In mice the conjugate is devoid of acute toxicity even at high dose (1.3 mg/g) and injected i.m. for 20 days does not induce antibodies. Moreover it is highly soluble in water; this means that a pharmacologically active dose may be administered in a small volume compatible with the i.m. route. Compared to the similar ara-AMP complex with lactosaminated albumin which must be injected intravenously, the present conjugate might assure a better compliance of patients with hepatitis B virus infection for a long lasting, liver targeted antiviral treatment.

Amino Sugars↗
PubMed1993

Coupling of antiviral nucleoside analogs to lactosaminated human albumin by using the imidazolides of their phosphoric esters.

Liver targeting of antiviral nucleoside analogs can be obtained by conjugating these drugs with the hepatotropic molecule lactosaminated serum albumin. We describe a new coupling procedure which uses the imidazolides of the phosphoric ester derivatives of the drugs in an alkaline medium. By this procedure conjugates are obtained with a high drug/carrier molar ratio and without the unwanted protein chemical changes produced by carbodiimides usually employed for this coupling.

Animals↗
PubMed1993

[The physiopathology and therapy of esophageal diverticula].

The authors report their experience in the management of 14 patients affected by esophageal diverticula and surgically treated (9 had cervical diverticula, 2 had epibronchial diverticula and 3 had epiphrenic diverticula). All these patients underwent a diverticulectomy: in 3 cases the diverticulectomy was associated with a subdiverticular myotomy. In the last three cases the resection of the diverticulum was performed using an automatic stapler. The follow-up of these patients was prolonged for a period of 5 years with clinical, radiographic and endoscopic evaluations performed at 6 monthly intervals. The most recently operated patient has a minimum follow-up of 22 months. There were no operative deaths and none of the patients complained of recurrence of the diverticulum or of the preoperative symptomatology. No significant complications were observed in the postoperative period in the patients who underwent a simple diverticulectomy or in the cases in which a subdiverticular myotomy was associated. The scant number of observed patients does not allow us to draw any conclusion about the necessity maintained by most authors of an associated myotomy. It is however evident that this adjunctive procedure doesn't cause any further difficulty and is not loaded with an increased risk of complications. Finally the authors believe in the usefulness of performing the diverticulectomy with an automatic stapler, these devices allow in fact a considerable reduction of the surgical time and prevent dangerous contaminations of the operative field.

Adult↗
PubMed1993

[Primary lymphoma of the gastrointestinal tract].

Lymphomas of the gastrointestinal tract are rare tumors with unusual features and few characteristics. Clinical, radiological and endoscopic diagnosis is difficult, because they may be confused with inflammatory or neoplastic forms, especially in primary involvement of the gastrointestinal tract. From 1965 we observed 4 patients with primitive gastrointestinal tract lymphomas. Prognostically important features for GI lymphomas were: stage, site of the primary disease, histological type. Authors report on the clinical findings, diagnostic procedures, surgical treatment and results.

Adolescent↗