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S Pace

Publications and source records attributed to S Pace.

At least 19 recordsLinked to original sources
PubMed2001

Potent antitumor activity and improved pharmacological profile of ST1481, a novel 7-substituted camptothecin.

Relevant drawbacks of the molecular structure and mechanism of the action of camptothecins are the instability of the E ring lactone and the reversibility of drug-target interaction. Such features are expected to limit the clinical efficacy of conventional camptothecins. In an attempt to overcome these limitations and to improve the pharmacological profile of camptothecins, a novel series of seven modified lipophilic analogues was synthesized based on the hypothesis that lipophilicity could promote a rapid cellular accumulation and stabilization of drug-target interaction. A novel analogue (ST1481) of the series, characterized by a potent antitopoisomerase and cytotoxic activity, was selected for preclinical development. A detailed preclinical study of ST1481 was performed in the H460 non-small cell lung tumor model using oral administration and various treatment schedules. Under all of the conditions, ST1481 exhibited an impressive efficacy in terms of tumor growth inhibition (tumor volume inhibition percentage > 99%), log(10) cell kill, rate of complete responses (including "cures"), and an improvement of the therapeutic index compared with topotecan (used as the reference drug). The cytotoxic potency was also reflected by the in vivo potency, because the drug activity was observed at doses as low as 0.25 mg/kg with the daily schedule. In contrast to topotecan, no cross-resistance to ST1481 was found in ovarian carcinoma cells overexpressing P-glycoprotein (A2780/DX). A similar trend in the improvement of activity was also observed in the same tumor model growing in vivo with a 100% rate of complete tumor regressions. A rapid intestinal absorption and good oral bioavailability were supported by in vivo distribution studies, because the peak values of drug accumulation were found from 1 to 2 h after administration. The relevant liver accumulation may account for a marked effect of ST1481 against liver metastases induced by the ovarian carcinoma IGROV-1. In conclusion, the results support the hypothesis that a potent lipophilic camptothecin with a proper substituent at the position 7 may have therapeutic advantages likely related to a rapid intracellular uptake and tissue distribution, stabilization of the drug-target complex, and good oral bioavailability. Overall, the results support the preclinical interest of ST1481 in terms of efficacy, potency, toxicity profile, and ability to overcome multidrug resistance.

Administration, Oral↗
PubMed2001

Characteristics of irreversible ATP activation suggest that native skeletal ryanodine receptors can be phosphorylated via an endogenous CaMKII.

Phosphorylation of skeletal muscle ryanodine receptor (RyR) calcium release channels by endogenous kinases incorporated into lipid bilayers with native sarcoplasmic reticulum vesicles was investigated during exposure to 2 mM cytoplasmic ATP. Activation of RyRs after 1-min exposure to ATP was reversible upon ATP washout. In contrast, activation after 5 to 8 min was largely irreversible: the small fall in activity with washout was significantly less than that after brief ATP exposure. The irreversible activation was reduced by acid phosphatase and was not seen after exposure to nonhydrolyzable ATP analogs. The data suggested that the channel complex was phosphorylated after addition of ATP and that phosphorylation reduced the RyR's sensitivity to ATP, adenosine, and Ca(2+). The endogenous kinase was likely to be a calcium calmodulin kinase II (CaMKII) because the CaMKII inhibitor KN-93 and an inhibitory peptide for CaMKII prevented the phosphorylation-induced irreversible activation. In contrast, phosphorylation effects remained unchanged with inhibitory peptides for protein kinase C and A. The presence of CaMKIIbeta in the SR vesicles was confirmed by immunoblotting. The results suggest that CaMKII is anchored to skeletal muscle RyRs and that phosphorylation by this kinase alters the enhancement of channel activity by ATP and Ca(2+).

Acid Phosphatase↗
PubMed2001

Successful diagnostic and surgical hysteroscopy for endometrial ossification.

PURPOSE OF INVESTIGATION: Diagnostic-operative hysteroscopy was successful in two cases of endometrial ossification, and fertility was restored. METHODS: A 30-year-old and a 32-year-old woman presented at our Department with a history of secondary infertility, complaining of pelvic pain, dysmenorrhea and polymenorrhea which lasted for about one year before admission. Previous ultrasound studies revealed the presence of two bright hyperechogenic bands with posterior shadowing. RESULTS: In both cases diagnostic-operative hysteroscopies were performed, displaying osseous fragments which were removed with resectoscopy, mainly mechanically. CONCLUSION: Hysteroscopic resection should be the elective treatment for endometrial ossification because it allows complete removal of osseous fragments and reduces the chance of residual synechia. The mean objective of hysteroscopy in endometrial ossification is the restitution of conceivement capability.

Adult↗
PubMed2000

Efficacy and toxicity profile of oral topotecan in a panel of human tumour xenografts.

On the basis of their mechanism of action (cell killing during DNA replication) and the potential reversibility of the drug effects, protracted therapy with camptothecins is reported to provide optimal antitumour effects. Furthermore, oral administration may be a useful modality for optimisation of treatment. The aim of this study was to compare the therapeutic profile of topotecan given orally or intravenously in human tumours xenografted into athymic nude mice. The drug topotecan was given according to an intermittent (every fourth day, four times) or daily (qdx5/weeklyx5-10 weeks; only orally) schedule. Tumour growth inhibition and persistence of drug effects were assessed and compared with untreated mice. In a panel of seven tumour xenografts, oral topotecan was at least as effective on three and significantly more effective on four tumours. Using the intermittent schedule, the maximum tolerated dose (MTD) was comparable for the two routes (15 mg/kg), but the toxicity profile suggested a better tolerability in terms of lethal effects after oral administration. The daily oral treatment of low drug doses allowed a higher cumulative dose to be delivered with improved antitumour efficacy (2/10 cured in a large cell lung cancer) and no evidence of toxicity. In spite of the low bioavailability of oral topotecan (23.5%), the persistent plasma levels of the drug suggest that the time of exposure to the drug is more critical than the plasma concentrations for antitumour efficacy. This interpretation is consistent with the increased efficacy of prolonged daily treatment with low-dose levels. The results may have implications for the future design of clinical studies.

Administration, Oral↗
PubMed2000

Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption.

AIMS: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.

Absorption↗
PubMed2000

Pharmacokinetics of L-carnitine in patients with end-stage renal disease undergoing long-term hemodialysis.

OBJECTIVE: L-Carnitine is an endogenous molecule involved in fatty acid metabolism. Secondary carnitine deficiency may develop in patients with end-stage renal disease undergoing long-term hemodialysis because of dialytic loss. In these patients L-carnitine can be administered to restore plasma and tissue levels. The objective of this study was to evaluate the pharmacokinetics of intravenous L-carnitine in patients undergoing long-term hemodialysis. METHODS: Twelve patients undergoing three dialysis sessions/week received L-carnitine intravenously (20 mg x kg(-1)) at the end of each dialysis session for 9 weeks. Plasma samples were analyzed for L-carnitine, acetyl-L-carnitine, and total carnitine by HPLC. RESULTS: Under baseline conditions, the mean +/- SD predialysis plasma concentration of L-carnitine was 19.5 +/- 5.6 micromol/L, decreasing to 5.6 +/- 1.9 micromol/L at the end of the dialysis session. These concentrations were substantially lower than endogenous levels in healthy human beings. Under baseline conditions the extraction ratios of L-carnitine and acetyl-L-carnitine by the dialyser were 0.74 +/- 0.07 and 0.71 +/- 0.11, respectively. During repeated dosing, there was accumulation of L-carnitine in plasma, and after 9 weeks of dosing, the predialysis and postdialysis plasma levels were 191 +/- 54.1 and 41.8 +/- 13.0 micromol/L, respectively. The predialysis and postdialysis plasma levels of L-carnitine decreased once dosing was ceased but had not returned to pretreatment levels after 6 weeks. CONCLUSION: The study demonstrated that removal of L-carnitine by hemodialysis is extremely efficient and that patients undergoing hemodialysis had plasma concentrations that were substantially lower than normal, particularly during dialysis. During repeated administration of L-carnitine, the predialysis and postdialysis concentrations of the compound increased steadily, reaching an apparent steady state after about 8 weeks. It is proposed that this accumulation arose from the distribution of L-carnitine into a deep tissue pool that includes skeletal muscle.

Acetylcarnitine↗
PubMed1999

Gastrosparing effect of new antiinflammatory drug amtolmetin guacyl in the rat: involvement of nitric oxide.

The effect of the nonsteroidal antiinflammatory drug (NSAID) amtolmetin guacyl (AMG) on the gastric mucosa was studied in the rat by means of histological and functional techniques. AMG administered at 50-300 mg/kg intragastrically was virtually devoid of gastrolesive properties after either acute or repeated treatment. By contrast, its metabolite, tolmetin (TOL, 15-60 mg/kg, intragastrically) caused dose-dependent gastric damage after both treatments. Light and electron microscopy revealed that AMG induced minimal changes in the surface epithelium layer, without signs of vasocongestion or leukocytes adherence. AMG (50 mg/kg intragastrically) did not change basal gastric potential difference (PD), whereas acetylsalicylic acid and ibuprofen induced falls in PD of 22 and 27 mV, respectively. AMG (50 mg/kg intragastrically) reduced by 60% the fall in PD induced by 50% ethanol; this inhibition was dependent on the incubation time, and was maximal when AMG was given 4 hr before ethanol. AMG (100 mg/kg intragastrically) induced an increase in NO synthase type 2 (NOS2) activity, which was significantly different from control values, when AMG was administered 4 hr before the test. The metabolites of AMG, tolmetin, MED 5, and guaiacol were ineffective. Pharmacokinetic analysis of the residence time of AMG in the different areas of the gastrointestinal tract, revealed that AMG remains in the gastrointestinal tract at least for 4 hr, the time necessary for a maximal induction of NOS2 and for maximal protection against ethanol-induced damage. In conclusion, these data indicate that the nonsteroidal antiinflammatory drug amtolmetin guacyl is devoid of gastrolesive properties; this gastro-sparing effect seems to involve the production of nitric oxide, which can counteract the damaging effects due to prostaglandin inhibition. The presence in the stomach of the native molecule of amtolmetin guacyl seems to be necessary for the protective effect observed.

Animals↗
PubMed1997

Pearls, pitfalls, and updates in toxicology.

Pearls and pitfalls learned from our practical experiences caring for poisoned patients are presented. Clinical pearls include the following: using diagnostic tests to detect end-organ toxicity, applying physiologic principles to the management of hemodynamically unstable poisoned patients, and dealing with psychologic injuries from hazardous materials incidents. Recognizing serious complications from poisoning and adverse drug effects, including the serotonin syndrome, are offered as pitfalls. Pharmaceutical companies are rapidly developing and marketing new therapies. Therefore, updates on the evolving role of NAC as an antidote for acetaminophen poisoning, new psychotropic medications, and new antidotes were included in this article. These pearls, pitfalls, and updates are intended to provide practical information that is readily applicable to the clinical practice of emergency medicine.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

Cervical intraepithelial neoplasia and bacterial vaginosis: correlation or risk factor?

Bacterial Vaginosis (B.V.) is a syndrome defined microbiologically where lactobacilli-dominated flora is exchanged with an abundant complex flora dominated by strict and facultative anaerobic bacteria, constituted by gardenerella, micrococci, streptococci and staphylocci. It has been suggested that B.V. could be important in the development of cervical intracpithelial neoplasias, because the abnormal micro flora can produce careinogenic nitrosamines. The aim of this investigation was to evaluate the correlation between CIN and B.V. in 1,008 patients (median age: 28 years, range 17-60) who were divided into two groups: the first group consisted of 504 patients affected by CIN of different degrees, the second of 504 patients without CIN. All patients were submitted to colposcopy, pap-tests, cytology of the cervical canal and microcolpohysteroscopy in the case of lesions invading the cervical canal. The diagnosis of B.V. is based on four criteria: presence of clue cells, pH 4.5, positive amine test and increased vaginal discharge. X2 Pearson analysis was applied for statistical evaluation of the data. Among the 504 patients in the first group (women affected by CIN of different degrees), 180/504 (36%) women presented B.V. Among the second group (504 women without CIN), 248/504 (49%) women presented B.V. The results of our study demonstrate that there is no significant correlation between CIN and B.V. In the first group of patients affected by CIN and B.V., B.V. was present in 36% of the cases, while in the second group of patients not affected by CIN. B.V. was present in 49% of the cases (P < 0.00005).

Adolescent↗
PubMed1997

[Diagnostic and therapeutic problems in tubal adenocarcinoma. Report of a case].

Primary adenocarcinoma of the Fallopian tube is one of the most rare tumours: its incidence varies from 0.5% to 1.1% of all gynecological neoplasias. In 1988 a total of 1,200 cases had been reported, the majority grouped in small series and/or individual case reports. The first case was reported by Renauld in 1847. The preoperative diagnosis has increased over the past forty years from 0.26% to 6.38%, and is still extremely low. The diagnosis of primary adenocarcinoma of the uterine tube is basically achieved by exclusion, and in fact the metastasization of the tubes by adjacent gynecological organs must be excluded. The trio of abdominal pain, leukorrhea, metrorrhagia is regarded by many authors as being pathognomonic of tubal adenocarcinoma. In about half of patients the interval between the onset of symptoms and histological diagnosis is 2-3 months, and in 30% less than one month. The authors report their experience of a case in a 62-year-old patient with typical symptoms of primary tubal adenocarcinoma.

Adenocarcinoma↗
PubMed1997

[Preliminary diagnostic evaluation of submucosal myoma using operative hysteroscopy].

BACKGROUND AND AIM: The authors aim to underline the importance of preliminary diagnostic evaluation in the treatment of submucous leiomyoma using hysteroscopy. MATERIALS AND METHODS: The study examined 18 patients monitored at the Institute of Obstetrics and Gynecology of "La Sapienza" University of Rome between January and December 1995 in whom it was possible to make a correct definition of the lesion to be treated (number, site, size, etc.) using 3 different diagnostic methods: hysteroscopy (HS), transvaginal scan (TSV) and transvaginal echohysterography (TVHS) The authors focused attention on three different parameters: leiomyoma size, extension (intracavity/intramural portion) and evaluation of the residual leiomyoma, which are essential for optimal endoscopic resection. RESULTS: HS enabled the number, size, site, origin, base, submucous portion and relations with tube operings to be evaluated, but did not allow the myometrial part of the lesion to be examined. CONCLUSIONS: Integration with TSV, even if this does not allow a precise definition of the extension, highlights the size, site, involvement of myometrial structure and relations with the perimetrium, thus allowing the possibility of evaluating the residual myometrium. Compared to the above methods, TVHS highlights the effective extension (namely the submucous/intramural portion) and localization of the neoformation.

Adult↗
PubMed1996

Intravenous morphine for early pain relief in patients with acute abdominal pain.

OBJECTIVE: To determine whether morphine affects evaluation or outcome for patients with acute abdominal pain. METHODS: Prospective, double-blind, placebo-controlled administration of morphine sulfate (MS) or normal saline (NS) in the setting of acute abdominal pain. The study was performed at a military ED with an annual census of 60,000 visits. Patients > or = 18 years old who had abdominal pain for < or = 48 hours were included. Patients who were allergic to MS or who had systolic blood pressures < 90 mm Hg were excluded. The physicians indicated a provisional diagnosis, a differential diagnosis, and a provisional disposition. Study solution was titrated to the patient's assessment of adequate analgesia (up to a volume equivalent of 20 mg of MS); pain response was monitored using a visual analog scale (VAS). The patients were followed until diagnosis occurred or symptoms resolved. RESULTS: Of 75 patients enrolled, 71 completed the study; 35 patients received MS and 36 received NS. More than half (44; 62%) of the patients were admitted from the ED; 28 patients underwent surgery. The VAS pain level improved more for the MS group, 3.9 +/- 2.8 cm, than it did for the NS group, 0.8 +/- 1.5 cm (p < 0.01). Study solution dose was less in the MS group than it was in the NS group, 1.5 +/- 0.5 mL vs 1.8 +/- 0.4 mL (p < 0.01). There was no difference between the groups when comparing accuracy of provisional or differential diagnosis with that of final diagnosis. Differences between provisional and actual dispositions were the same in all groups. There were 3 diagnostic or management errors in each group. CONCLUSIONS: When compared with saline placebo, the administration of MS to patients with acute abdominal pain effectively relieved pain and did not alter the ability of physicians to accurately evaluate and treat patients.

Abdomen, Acute↗
PubMed1995

[Hysteroscopy in septate uterus. Diagnostic and therapeutic features].

Personal experience of diagnostic and operative hysteroscopy of septate uterus is reported. The diagnosis of septate uterus is an integrated diagnosis that makes use of hysterosalpingography, echography, hysteroscopy and laparoscopy. Of 545 hysteroscopies carried out between January and December 1993, 29 evidenced uterine septum, complete in 6 cases, incomplete in the remaining 23. Of the 29 patients, 7 underwent resection of the septum by the hysteroscopic route. No intra or postoperative complications worthy of note were observed. At follow-up after one month, the uterine cavity in 5 patients proved completely regular while in the remaining 2 one case of fundic fibrous synechia and one of small persistent fibrous bridge, of little importance within the context of the cavity, were observed. The purpose of the present paper is to demonstrate the twofold role of hysteroscopy with regard to the septate uterus; is that hysteroscopy is a diagnostic and a precise operative technique that is atraumatic, fast and of low cost.

Adolescent↗
PubMed1995

Cervical intraepithelial neoplasia: carbon dioxide laser vaporization and conization. Our experience.

Between 1984 and 1992, the CO2 laser was used to treat 341 patients affected by CIN of various degrees. On the basis of specific indications these patients underwent vaporization or conization. Two hundred and twenty eight patients underwent vaporization of intraepithelial lesions, 221 (96.92%) of whom were free of disease after one laser treatment, as observed during the subsequent years of follow-up. In 105 out of the 113 patients treated with conization the cone margin was free of disease. One hundred and one (96.19%) of the these 105 patients had no evidence of disease after one year of follow-up. In the remaining 8 (7.07%) cases examination of the cone revealed the presence of invasive carcinoma. The major complication was vaginal discharge observed in 115 (33.72%) patients. The CO2 laser is a very effective therapeutic procedure for the treatment of intraepithelial lesions of the cervix and permits to preserve reproductive function and anatomic integrity.

Adolescent↗
PubMed1995

Diagnostic methods of early detection of endometrial hyperplasia and cancer.

Endometrial carcinoma is the most frequent genital neoplasia in women. Our own experience is based on a group of 3310 patients who were studied between 1985 and April 1994. In 2148 cases, equivalent to 56.4%, hysteroscopy was performed because of the presence of abnormal uterine bleeding (AUB). We found 672 endometrial hyperplasia (601 low risk-71 high risk) and 93 endometrial carcinoma. According to our experience we can assert that: hysteroscopy allows the measurement of the extension of the intracavitary neoplastic pathology and the definition of its topographic map; it is the only method that allows a target biopsy; it facilitates the evaluation of the extension of the neoplasia in the cervical canal, with the help of a deep biopsy into the cervical tissue (as proposed by La Sala) increasing its diagnostic accuracy.

Aged↗