Daily Continuous Infusion Research Articles

Neuropeptide Y delays hippocampal kindling in the rat.

Chronic intrahippocampal infusion of the neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to delay kindling epileptogenesis in the rat and several lines of evidence suggest that neuropeptide Y could mediate these inhibitory effects. Chronic infusion of BDNF leads to a sustained overexpression of neuropeptide Y in the hippocampus, which follows a time course similar to that of the suppressive effects of BDNF on kindling. In vivo, acute applications of neuropeptide Y or agonists of its receptors exert anticonvulsant properties, especially on seizures of hippocampal origin. In this study, we examined how chronic infusion of this neuropeptide in the hippocampus affected kindling epileptogenesis. A 7-day continuous infusion of neuropeptide Y in the hippocampus delayed the progression of hippocampal kindling in the rat, whereas anti-neuropeptide Y immunoglobulins had an aggravating effect. These results show that neuropeptide Y exerts anti-epileptogenic properties on seizures originating within the hippocampus and lend support to the hypothesis that BDNF delays kindling at least in part through upregulation of this neuropeptide. They also suggest that the seizure-induced upregulation of neuropeptide Y constitutes an endogenous mechanism counteracting excessive hippocampal excitability.

Dose intensity and clinical response in head and neck carcinoma treated with cisplatin + 5-fluorouracil

Chemotherapy dose adjustment has been associated with cancer treatment failure in some types of cancer. The aim of this study was to evaluate the impact of dose intensity in the efficacy of neoadjuvant treatment of locally advanced squamous cell carcinoma of head and neck (SCCHN).We reviewed the records of seventy patients with locally advanced SCCHN (stage III or IV) treated with three cycles of CDDP (100 mg/m2) plus 5-day continuous infusion of 5-FU (1,000 mg/m2/day) before local therapy. Planned and received dose intensity were both calculated, and clinical response and survival were assessed.Median dose intensity received was 28.38 mg/m2/week for CDDP (range: 7.45–35) and 278.16 for 5-FU (range: 74.47–350). Overall response rate to the chemotherapy combination was 76%. Cisplatin was administered ≥75% of the planned dose in 80% of the patients, and 5-FU was administered ≥75% in 76% of cases. The response rate was significantly higher in the patients that received ≥75% of the planned dose of CDDP (82% vs 50%, p=0.004), and in patients receiving ≥75% of the planned dose of 5-FU (83% vs 53%, p=0.028). Overall survival also correlated with the dose intensity of chemotherapy. Median survival of patients receiving ≥75% of CDDP was significantly longer that patients receiving <75% of CDDP (32 vs 18 months, p=0.03). Similarly, median survival of patients receiving ≥75% of 5-FU was significantly longer that patients receiving <75% of 5-FU (33 vs 21 months, p=0.02).Maintaining a dose-intensity of CDDP and 5-FU above 75% in patients with locally advanced head and neck cancer results in an improved treatment benefit, both in terms of response rate and overall survival.

Time-intensified dexamethasone/cisplatin/cytarabine:an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease

BackgroundAn important variable affecting outcome in relapsed and refractory Hodgkin’s disease (HD) is the potential of conventional salvage chemotherapy to reduce tumor volume before high-dose chemotherapy (HDCT) and autologous stem cell transplantation. Currently, the optimal salvage chemotherapy regimen for these patients is unclear. Since dexamethasone/cisplatin/cytarabine (DHAP) given at 3–4 week intervals has been shown to be very effective in patients with relapsed aggressive non-Hodgkin’s lymphoma, we evaluated this regimen given at a median of 16-day intervals in patients with relapsed and refractory HD. Patients and methodsPatients with relapsed or refractory HD were treated with two cycles of DHAP [dexamethasone 40 mg intravenously (i.v.) day 1–4, cisplatin 100 mg/m2 i.v. as 24-h continuous infusion day 1, and cytarabine 2 g/m2 i.v. 12q day 2]. Granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 µg/kg from day 4 until day 13. Patients with partial remission (PR) or complete remission (CR) after two cycles of DHAP received sequential HDCT. ResultsThe median age of the 102 patients included was 34 years (range 21–64 years). Forty-two percent of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate (RR) after two cycles of DHAP was 89% (21% CR, 68% PR). The RRs for patients with late, early, multiple and progressive HD were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HD versus progressive HD) and stage at relapse (stage I/II versus stage III/IV) were significant factors forresponse to DHAP. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxic- ities occurring in 43% (mean duration 1.1 days, range 0–6) and 48% (mean duration 1.4 days, range 0–11) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells (PBSCs) were collected after the first cycle DHAP in eight patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 × 106/kg CD34+ cells were collected per apheresis. As originally recommended in the protocol, PBSCs were routinely collected during sequential HDCT in the remaining patients. ConclusionsA brief tumor-reducing program with two cycles of DHAP given in short intervals supported by G-CSF is effective and well-tolerated in patients with relapsed and refractory HD. This regimen can be used to mobilize stem cells and select those patients with chemosensitive relapse who should subsequently be treated with HDCT.

SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile.

The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.

Neurotrophins Reduce Degeneration of Injured Ascending Sensory and Corticospinal Motor Axons in Adult Rat Spinal Cord

Spinal cord regeneration in adult mammals is limited by neurite outgrowth inhibitors and insufficient availability of outgrowth-promoting agents. Formation of degenerative swellings at the proximal ends of severed axons (terminal clubs), which starts early after injury, also may hinder recovery and their rupture may contribute to secondary spinal cord damage. We investigated whether neurotrophins would reduce these degenerative processes. Adult rats received a transection of the dorsal column sensory and corticospinal motor tracts at T9 and anterograde tracing of the axons from the sciatic nerve and motor cortex, respectively. The highest number of terminal clubs was found at 1 day and approximately half remained present until at least 28 days. A single injection immediately after injury of a mixture of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 into the lesion site, reduced the number of terminal clubs in the sensory system by approximately half at 1 and 7 days (but not 14) after the lesion. Individual or combinations of two neurotrophins were as effective, suggesting that the neurotrophins protected similar axonal populations. The injected neurotrophins did not affect degeneration of corticospinal motor axons. A 7-day continuous intrathecal infusion of neurotrophin-3 was more effective and also reduced terminal club formation of corticospinal axons by ∼60%. Spinal tissue loss was not affected by the neurotrophin treatments, suggesting that terminal clubs are not major contributors to the pathogenesis of secondary spinal degeneration during the first two weeks. Thus, neurotrophins can reduce axonal degeneration in the spinal cord after traumatic axonal injury.

A Phase II Study of the Immunotoxin N901-Blocked Ricin in Small-Cell Lung Cancer

This study was designed to evaluate the efficacy and toxicity of the immunotoxin N901-blocked ricin (bR) in patients with small-cell lung cancer (SCLC) who achieved a complete or near-complete response following chemotherapy and/or radiation. Treatment consisted of a 7-day continuous infusion of N901-bR at a dose of 30 μg/kg/day followed by patient evaluation with repeat scans. Serum immunotoxin levels, human antimurine antibodies, and antiricin antibodies were determined during the course of the infusion. Nine patients enrolled in the study before it closed following a treatment-related death. Seven patients had extensivestage disease and entered the study with a more than 90% reduction of their original tumor. Two patients with limited-stage SCLC had no evidence of disease at study entry. Maximum plasma levels of N901-bR ranged from 72-371 ng/mL. Laboratory toxicity consisted of transient transaminitis in 8 patients and creatine kinase elevation in 3 patients, 1 of whom developed premature ventricular contractions. One patient experienced progressive capillary leak syndrome following immunotoxin infusion, which proved fatal. All patients developed antibodies to the infused murine antibody as well as to the toxin. Six patients died of progressive SCLC and 1 patient died of presumed radiation pneumonitis. One patient with limited-stage disease is still alive more than 6 years after therapy. N901-bR therapy was associated with a fatal incident of capillary leak syndrome and a nearly universal development of human antimouse and antiricin antibodies, which limited its further clinical development.

Phase I/II clinical trial of concurrent radiochemotherapy in combination with topotecan for the treatment of brain metastases

The prognosis of patients with brain metastases is very poor. In this phase I/II study we tested the feasibility, dosage, toxicity and tumour efficacy of a concurrent radiochemotherapy regimen including topotecan. Twenty patients were recruited between July 1998 and February 2000 (9 women, 11 men) and treated with a whole-brain irradiation of 40 Gy (some patients were also given a boost) in combination with topotecan given as a 21-day continuous infusion in a dosage of 0.4 to 0.6 mg/m2/day. The median survival was five months (95% Confidence Interval (CI): 2–8 months). In 13 of 20 patients, it was possible to evaluate the remission with computed tomography (CT) scans or magnetic resonance scans. We detected four complete responders (CRs), two partial responders (PRs), and one progressive disease (PD). 6 patients had stable disease (SD). An intracerebral recurrence was experienced in 3 patients, 3 patients experienced spinal lesions. Systemic progression of cancer outside the central nervous system (CNS) was dominant in 9 of 20 patients. A reversible, non-cumulative haematological toxicity mainly occurring from a dose of 0.5 mg/m2/day and above was dose-limiting for this type of therapy. Combined concurrent radiochemotherapy with topotecan is feasible in spite of various pretreatments. Myelosuppression was the dominant toxicity, which was reversible and manageable. We recommend a dose of 0.4 mg/m2/day of topotecan as a 21-day continuous infusion therapy in combination with radiotherapy.

Effects of short-chain fatty acid-supplemented total parenteral nutrition on intestinal pro-inflammatory cytokine abundance.

We examined the effect of short-chain fatty acid-supplemented total parenteral nutrition on proinflammatory cytokine levels in piglets. Piglets (N = 22) received either standard total parenteral nutrition or total parenteral nutrition supplemented with short-chain fatty acids. After seven days of continuous nutrient infusion, proinflammatory cytokine (TNF-alpha, IL-1beta, IL-6) abundance in plasma, jejunal, and ileal samples and small intestinal myeloperoxidase was determined using western blotting. No differences were seen in TNF-alpha small intestinal abundance. IL-1beta was higher in the small intestine of the short-chain fatty acid group (P < 0.05). IL-6 was higher in intestinal samples of the short-chain fatty acid group (P = 0.05), with the ileum having a greater abundance of IL-6 than the jejunum (P < 0.005). No differences in proinflammatory cytokine abundance in the plasma or tissue myeloperoxidase were seen. These results indicate short-chain fatty acids beneficially increase small intestinal abundance of IL-1beta and IL-6 during total parenteral nutrition administration, while not affecting systemic production of these cytokines or intestinal inflammation.

Combination Therapy Stroke Trial: Recombinant Tissue-Type Plasminogen Activator with/without Lubeluzole

Background: A neuroprotective drug may be safe and effective if given very early and in combination with recombinant tissue-type plasminogen activator (rt-PA) to acute stroke patients. No clinical trial has yet tested this hypothesis. Objective: To assess the feasibility, safety and efficacy of simultaneously combining the neuroprotective drug lubeluzole with rt-PA. Method: Patients who qualified for and received rt-PA within 3 h of symptom onset were randomly allocated 1:1 to lubeluzole (7.5 mg i.v. over 1 h, then continuous 5-day infusion of 10 mg/day) or placebo. Infusion of the study medication was started before the end of the 1-hour rt-PA infusion. Inclusion criteria were the same as those of the FDA-approved guidelines for rt-PA, plus National Institutes of Health Stroke Scale (NIHSS) >5 and absence of serious ventricular arrhythmia, atrioventricular block or Q–T >450 ms. EKG was continuously monitored until 48 h after treatment. The primary outcomes were adverse events, especially hemorrhage and severe arrhythmia, and functionality as determined by the Barthel Index divided into >70,0–70 and dead. Results: 89 patients were randomized at 34 centers over 8 months. The study was terminated by the sponsor before the planned enrollment of 200 patients when a concurrent phase 3 trial of lubeluzole versus placebo given up to 8 h after stroke was negative. In our study, the mean NIHSS was 14.5, and the mean time from symptom onset to rt-PA was 2.5 h and to randomization to lubeluzole or placebo 3.2 h. Mortality was 26%, intracerebral hemorrhage occurred in 10% and serious adverse events in 51%. There were no differences between the two treatment groups in any of these variables, outcomes or in the Barthel Index or other measures of functionality. Conclusion: Combining neuroprotective drugs such as lubeluzole simultaneously with rt-PA is feasible and safe. The efficacy of this strategy, using a potentially more effective neuroprotective agent, should be evaluated in an adequately powered clinical trial.

Glucocorticoid inhibition of neuropathic limb edema and cutaneous neurogenic extravasation

Sciatic nerve section in rats evokes chronic limb edema, pain behavior, and hindpaw hyperalgesia, a syndrome resembling the complex regional pain syndrome type II (CRPS II or causalgia) in man. Glucocorticoids such as methylprednisolone (MP) have been used as analgesic and anti-edematous agents in patients suffering from CRPS, and interestingly these therapeutic effects appear to persist in some patients after stopping the medication. Similar to the CRPS clinical response to glucocorticoids, we now demonstrate that chronic hindpaw edema in the sciatic transection CRPS model is reversed by a continuous infusion of MP (3 mg/kg/day over 21 days), and this anti-edematous effect persists for at least 1 week after discontinuing MP. Furthermore, there is a chronic increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous hands of CRPS patients. A 2-week infusion of MP (3 mg/kg/day) reduced spontaneous protein extravasation in the hindpaw skin by 80%. We postulated that increased spontaneous neurogenic extravasation resulted in development of limb edema in both the animal model and the CRPS patient, and that the anti-edematous effects of MP are due to an inhibition of spontaneous extravasation. Additional experiments examined the inhibitory effects of MP infusion on electrically-evoked neurogenic extravasation in the hindpaw skin of normal rats. MP inhibition was dose- and time-dependent, with an ED 50 of 1.2 mg/kg/day for a 14-day continuous infusion of MP, and a maximum inhibitory effect requiring 17 days of MP infusion (3 mg/kg/day). MP (3 mg/kg/day for 14 days) also blocked both capsaicin- and SP-evoked neurogenic extravasation, indicating a post-junctional inhibitory effect. Our interpretation is that increased spontaneous neurogenic extravasation in this CRPS model contributed to the development and maintenance of hindpaw edema, and that chronic MP administration dose- and time-dependently blocked neurogenic extravasation at a post-junctional level, thus reversing spontaneous extravasation and limb edema in this model.

Radiothérapie bifractionnée et chimiothérapie par cisplatine et 5-fluoro-uracile concomitantes dans les carcinomes épidermoïdes localement évolués non résécables du pharynx : dix ans d’expérience au centre Antoine Lacassagne

Purpose. – Patients suffering from locally advanced unresectable squamous cell carcinoma of the oropharynx and hypopharynx treated with radiotherapy alone have a poor prognosis. More than 70% of patients die within 5 years mainly due to local recurrences. The aim of this study was to evaluate retrospectively the Antoine Lacassagne Cancer Center’s experience in a treatment by concomitant bid radiotherapy and chemotherapy. Evaluation was based on analysis of the toxicity, the response rates, the survival, and the clinical prognostic factors. Patients and methods. – From 1992 to 2000, 92 consecutive patients were treated in our single institution. All of them had stage IV, unresectable squamous cell carcinoma of the pharynx and they received continuous bid radiotherapy (two daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total radiotherapy dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Two or three chemotherapy courses of cisplatin (CP) -5-fluorouracil (5FU) were given during radiotherapy at 21-day intervals (third not delivered after the end of the radiotherapy). CP dose was 100 mg/m 2 (day 1) and 5-FU was given as 5-day continuous infusion (750 mg/m 2/day at 1st course; 430 mg/m 2/day at 2nd and 3rd courses). Special attention was paid to supportive care, particularly in terms of enteral nutrition and mucositis prevention by low-level laser energy. Results. – Acute toxicity was marked and included WHO grade III/IV mucositis (89%, 16% of them being grade IV), WHO grade III dermatitis (72%) and grade III/IV neutropenia (61%). This toxicity was significant but manageable with optimised supportive care, and never led to interruption of treatment for more than 1 week, although there were two toxic deaths. Complete global response rate at 6 months was 74%. Overall global survival at 1 and 2 years was 72% and 50% respectively, with a median follow-up of 17 months. Prognostic factors for overall survival were the Karnofsky index (71% survival at 3 years for patients with a Karnofsky index of 90–100% versus 30% for patients with a Karnofsky index of 80% versus 0% for patients with a Karnofsky index of 60-70%, p = 0.0001) and tumor location (55% at 3 years for oropharynx versus 37% for panpharynx versus 28% for hypopharynx, p = 0.009). Conclusion. – These results confirm the efficacy of concomitant bid radiotherapy and chemotherapy in advanced unresectable tumor of the pharynx. The improvement in results will essentially depend on our capacity to restore in a good nutritional status the patients before beginning this heavy treatment.

The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy

Purpose: To investigate the potential benefit of reducing the intersequence gap in patients with anal cancer treated with split-course chemoradiotherapy. Methods: The study group consisted of 90 patients with anal squamous carcinoma treated between 1981 and 1998, using concomitant chemotherapy (CT) and radiation (RT). Median age was 65 years (range 41–87). RT was delivered in a split course, with a median gap of 37.5 days (range 4–97) between sequences. First (pelvic) sequence delivered a median dose of 40 Gy (range 36–50.4), using AP/PA megavoltage photon beams. Boost treatment (median dose 20 Gy, range 13–26) consisted of either Iridium-192 implantation (49 patients) or external beam RT (41 patients). CT consisted of 1–2 cycles of a 5-day continuous infusion of 5-fluorouracil and bolus mitomycin C, usually administered during the first week of each RT course. Median follow-up was 76.2 months. Univariate and multivariate analyses were performed to determine the factors associated with locoregional control (LRC). Results: Five-year actuarial LRC was 72.5%. Factors associated with poorer LRC (univariate) were: age ≤ 65, male gender, and gap > 37.5 days. Number of CT cycles (1 vs. 2 or more), boost technique (brachytherapy vs. external), and T-stage were not significantly associated with LRC. In multivariate analysis, only age ( p = 0.01), and gap ( p = 0.02) retained their significance. In patients older than 65 years, LRC was 92.3% and 75% for shorter and longer gaps, respectively. In younger patients, the corresponding values for LRC were 73.7% and 50%. Conclusion: In anal cancers, split-course RT with > 50 Gy dose delivery is difficult to avoid because of acute toxicity. The present analysis suggests that shortening the gap contributes to optimizing LRC. Gaps longer than 5 weeks correlated with poorer LRC, with especially unsatisfactory results observed in younger patients.

Multimodal treatment for squamous cell carcinoma of the esophagus: results with two different strategies

The prognosis of patients with esophageal cancer treated with esophagectomy alone is disappointing. To improve these results, the addition of chemotherapy and/or radiotherapy to surgery has been proposed. Since 1992, we have enrolled patients with locally-advanced squamous-cell esophageal carcinoma in two successive studies to evaluate the feasibility and efficacy of preoperative chemotherapy and concomitant chemotherapy plus radiotherapy.Between 1992 and 1994, 29 patients were treated with three courses of cisplatin 100 mg/m2 on day 1, fluorouracil (5-Fu) (750 mg/m2/day) by continuous infusion days 1 through 5, and folinic acid (200 mg/m2/day) days 1 to 5. Cycles were repeated every 3 weeks. Since November 1996, 21 patients have been included in a 3-week intensive schedule with weekly cisplatin (30 mg/m2 on days 1, 8 and 15) and continuous infusion of 5-Fu (300 mg/m2, days 1 to 21) plus concurrent hyperfractionated radiotherapy (1.5 Gy twice daily, total dose of 45 Gy, for 3 weeks). In both studies, patients underwent esophagectomy 3 to 5 weeks after induction therapy.In the preoperative chemotherapy scheme, a clinical response was observed in 30% of patients and one patient had a pathological complete response (pCR). The resectability rate was 58%, and five patients (17%) died in the postoperative period. Median survival and 3-year survival rate were 10 months and 4%, respectively. In the chemoradiotherapy study, a clinical response was observed in 19 (90%) of patients. A complete resection was performed in 15 patients (71%) and 7 patients (43% of all resected tumors) had a pCR. There have been no treatment-related deaths. To date, the median survival and 3-year survival rate are 27 months and 41%, respectively. In the chemotherapy study, the most frequent acute high-grade (3 or 4) toxicities were mucositis, observed in 44% of cycles, while severe, esophagitis was detected in 66% of patients treated with chemoradiotherapy.In our experience, preoperative chemotherapy does not seems to improve the results obtained with esophagectomy alone; furthermore, this approach was related to a significant postoperative mortality. On the contrary, concomitant chemotherapy with hyperfractionated radiotherapy has demonstrated a high activity with an encouraging 3-year survival rate. In spite a high incidence of esophagitis, this schedule is feasible without increasing postoperatory risk.

Suppression of cell proliferation by tissue plasminogen activator during the early phase after balloon injury minimizes intimal hyperplasia in hypercholesterolemic rabbits.

Thrombus formation is a key component of the pathogenesis of restenosis after arterial balloon injury. The purpose of this study was to determine whether intimal hyperplasia could be attenuated by infusion of recombinant tissue plasminogen activator (tPA). Forty-two Kurosawa and Kusanagi hypercholesterolemic rabbits were divided into tPA (n = 20) and control (n = 22) groups, the former receiving 7 days of continuous tPA infusion (0.6 mg/kg/day) via ear veins. The walls of the common iliac arteries were injured using 2.5-mm balloon catheters and then examined histologically 7, 14, 21, and 28 days later. Cell proliferation was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA), and transforming growth factor (TGF)-beta immunohistochemistry was carried out to estimate cell proliferation and differentiation. It was observed that 28 days after balloon injury, intimal cross-sectional areas in the tPA group were significantly smaller than in controls (0.11 +/- 0.03 mm2 vs. 0.57 +/- 0.08 mm2, p < 0.01), as were ratios of the cross-sectional areas of the intima and media (0.21 +/- 0.07 vs. 1.06 +/- 0.18, p < 0.05). In addition, the numbers of PCNA-positive medial cells were significantly lower (0.06 +/- 0.01 vs. 0.36 +/- 0.08, p < 0.05) and TGF-beta-positive vessel wall areas were significantly smaller in tPA-treated animals 7 days after balloon injury (0.47 +/- 0.28% vs. 4.55 +/- 1.44%, p < 0.05). Thus infusion of tPA after arterial balloon injury appears to decrease medial cell proliferation and suppress intimal hyperplasia.

Long-term magnesium sulfate treatment as protection against hypoxic-ischemic brain injury in seven-day-old rats

Objective: Our purpose was to study the effects of long-term treatment with magnesium sulfate on hypoxic-ischemic brain damage in newborn rats. Study Design: Seven-day-old rat pups (n = 120) were exposed to unilateral carotid artery ligation and 2 hours of hypoxia (8% oxygen in 92% nitrogen). Neuronal loss was evaluated in 4 groups. The loading dose group (n = 25) received a bolus injection of 270 mg/kg magnesium sulfate intraperitoneally. The maintenance group (n = 26) received 3 days of continuous infusion of magnesium sulfate with a micro-osmotic pump at a rate of 72 mg/kg per hour. The loading dose–plus–maintenance group (n = 23) received both. The control group (n = 46) did not receive magnesium. Seven days after the injury the pups were killed and the brains were removed for analysis. Severity of neuronal loss was evaluated in the cerebral cortex and hippocampus and compared among groups by χ2 test. Results: Cyst formation resulting from necrosis was significantly decreased in the maintenance group (15%) and loading dose–plus–maintenance group (9%) but not in the loading dose group (52%) relative to the control group (46%). Severity of neuronal loss in the cerebral cortex and the hippocampus was also significantly improved in the maintenance group and the loading dose–plus–maintenance group but not in the loading dose group. Mortality rates were not different among the groups. Magnesium ion concentrations at 24 hours were significantly decreased from the preinfusion value of 0.49 ± 0.01 mmol/L in the control group (0.34 ± 0.03 mmol/L) but remained within normal ranges in the maintenance group (0.46 ± 0.02 mmol/L with a pump infusing 72 mg/kg per hour and 0.56 ± 0.05 mmol/L with a pump infusing 24 mg/kg hour). There was an inverse relationship between the maintenance dose and neuronal loss but not between the maintenance dose and mortality rate. Conclusion: Long-term magnesium administration had neuroprotective effects against hypoxia-ischemia in newborn rats. (Am J Obstet Gynecol 2001;184:185-90.)

Reduction of vasopressor requirement by hydrocortisone administration in a patient with cerebral vasospasm

A 67-yr-old female received hypertensive, hypervolaemic treatment for cerebral vasospasm after severe subarachnoid haemorrhage. After 3 days of continuous vasopressor infusion and despite adequate hydration and normal cardiac function, the phenylephrine dose had to be increased to obtain the same systolic blood pressure. This tachyphylaxis to phenylephrine infusion was probably caused by down-regulation of alpha adrenoceptors, and was reversed by giving i.v. hydrocortisone.

A Phase I trial of h-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma

Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer. A continuous intravenous infusion of ISIS 2503 was administered for 14 days every 3 weeks to 23 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 2503 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/kg/day of body weight was reached. Toxicity was scored by the National Cancer Institute's Common Toxicity Criteria, and tumor response was monitored after every two treatment cycles. Pharmacokinetic studies were performed in some of the patients up to, and including, the final dose of 10 mg/kg/day/day of body weight. Levels of H-ras mRNA expression also were determined in the circulating lymphocytes of some patients by quantitative reverse transcriptase-polymerase chain reaction. A total of 23 patients received 63 cycles of ISIS 2503 at escalating doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cycles. No consistent decreases in H-ras mRNA levels were observed in peripheral blood lymphocytes. ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Comparison of heparin and steroids in the treatment of moderate and severe ulcerative colitis

Unfractionated heparin has been found to reduce symptoms and improve healing as adjuvant therapy in patients with ulcerative colitis. The current study evaluated the efficacy and safety of unfractionated heparin in the treatment of ulcerative colitis in comparison with methylprednisolone. A multicenter randomized trial with blinded endpoint evaluation was conducted in patients hospitalized for moderate or severe ulcerative colitis. Patients were randomized to receive heparin as a continuous infusion or methylprednisolone (0.75-1 mg x kg(-1) x day(-1)). Twenty-five patients entered the study: 13 received methylprednisolone and 12 received heparin. By day 10, 69% of patients in the methylprednisolone group, but none in the heparin group, achieved significant improvement or remission. C-reactive protein levels significantly decreased in the methylprednisolone group but not in the heparin group. Three patients in the heparin group were withdrawn before day 10 because of an adverse event: rectal bleeding needing transfusion (2 cases) or surgery (1 case). The proportion of patients with persistent rectal bleeding at day 10 was 31% in the methylprednisolone group and 90% in the heparin group (P<0.05). Unfractionated heparin as monotherapy is not effective in the treatment of moderate or severe ulcerative colitis and is associated with significant bleeding complications.

Phase I–II Trial of Preoperative Chemoradiation in Locally Advanced Cervical Carcinoma

Background. 5-Fluorouracil and cisplatin are characterized by in vitro synergism as well as radiosensitization. A phase I–II study was carried out on patients with invasive cervical carcinoma (FIGO IIB–IIIA) undergoing concomitant chemoradiation with 5-fluorouracil and cisplatin followed by radical surgery.Methods. Twenty-six patients of 53 years median age, 24 with IIB tumor and 2 with IIIA tumor, all with squamous carcinoma, entered the study. The chemoradiation protocol included external radiotherapy to the pelvis: 39.6 Gy (180 cGy/daily); 5-fluorouracil: 1 g/m2/daily, in continuous intravenous infusion days 1–4 and 27–30; cisplatin: 20 mg/m2/daily days 1–4 and 27–30. Four weeks after the end of chemoradiotherapy, patients underwent restaging and then radical surgery with pelvic and lumboaortic lymphadenectomy.Results. Twenty-six patients are evaluable for acute toxicity and 24 are evaluable for objective and pathologic response. Grade 3–4 thrombocytopenia or leukopenia was observed in 6 patients and grade 3 acute gastrointestinal toxicity in 3. After chemoradiation CR and PR were observed in 64 and 36% of cases, respectively (CR + PR = 100%). Two patients were excluded from surgery for other diseases. The remaining 24 patients were operated on; 23/24 patients showed negative section margins. The histology of the surgical specimen showed the absence of disease in 13 patients (54.2%), microscopic residual tumor in 4 patients (16.6%), residual disease ≤1 cm in 5 patients, and residual disease >1 cm in 2 patients. Median follow up was 33 months. Two-year actuarial local control was 91.7%.Conclusions. This study showed a particularly high rate of pathologic responses (complete + Tmic: 70.8%) and local control (2 years = 91.7%) in patients with advanced cervical cancer undergoing moderate doses of radiotherapy with concomitant chemotherapy followed by radical surgery.