A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma.

BACKGROUND: This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5-fluorouracil (5-FU)-based chemotherapy. METHODS: CPT-11 was given as a 90-minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicities between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age > or = 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS: CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicities. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.

Clinical pharmacology of nicorandil in patients with congestive heart failure.

Nicorandil is a nicotinamide derivative with a potential role in human therapeutics because of its potent vasodilating properties. The pharmacokinetics of oral nicorandil administration and the relationships between plasma nicorandil concentration and hemodynamic responses were examined in 25 patients with moderate to severe congestive heart failure. The dose range from 10 to 60 mg was studied. Elimination half-life for this dose range was substantially longer than that previously reported in normal volunteers. Total area under the curve increased in a curvilinear fashion with progressive dose increments, indicating a disproportionate increase in systemically available drug at higher doses. Hemodynamic responses generally correlated well with plasma nicorandil concentration, with rapid loss of cardiovascular activity corresponding to the efficient clearance of nicorandil.

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of oral nicorandil in congestive heart failure.

Twenty-five patients with congestive heart failure (CHF) underwent a double-blind randomized study of the acute hemodynamic effects of orally administered nicorandil, a newly developed vasodilator drug. A dose range of 10 to 60 mg was studied. Nicorandil, at a dose of 60 mg, caused statistically significant decreases in systemic systolic and diastolic blood pressure, right atrial pressure, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance and systolic and diastolic pulmonary arterial pressure. A brief increase in cardiac index attributable to an increase in stroke volume without a change in heart rate was also observed. A dose of 40 mg produced similar results in cardiac index and systemic and pulmonary vascular resistance, but changes in other hemodynamic parameters were much smaller in magnitude and usually not of statistical significance. No significant hemodynamic response was seen to doses of 10 and 20 mg of nicorandil. Duration of action was short with nearly all hemodynamic parameters returning close to baseline within 3 hours. This rapid decrease in activity occurred in concert with a rapid plasma clearance of nicorandil as determined by serial measurements of plasma drug concentration. This study suggests that first-dose orally administered nicorandil elicits favorable, but brief, hemodynamic effects in CHF at doses greater than or equal to 40 mg.

Multiple dose trial of the thromboxane synthase inhibitor furegrelate in normal subjects.

Furegrelate sodium, a pyridinyl derivative thromboxane synthase inhibitor, was evaluated for its effects on thromboxane synthesis in normal volunteers after multiple dose administration. Twenty-four subjects were randomized to 200, 400, 800 or 1600 mg furegrelate or placebo treatment BID for 4 1/2 days. Furegrelate (800 or 1600 mg) significantly inhibited thromboxane synthesis throughout the dosing interval as assessed by thromboxane B2 generation from platelet-rich plasma challenged with arachidonic acid or from serum. Platelet aggregation was inhibited, but the effect was variable and a clear dose response relationship was not apparent. Bleeding times were also variable but tended to increase at the higher doses. There was no clinically significant change in any coagulation parameters or in any safety laboratory evaluations. Peak serum concentrations occurred approximately 1 h after dosing; t1/2ke was approximately 2 h. There was no significant change in furegrelate's effects or pharmacokinetics over time (ie. Day 1 vs Day 5).

Thromboxane synthase activity and platelet function after furegrelate administration in man.

Furegrelate sodium (U-63,557A), a pyridine-derivative thromboxane synthase inhibitor, was administered orally in single doses of 200 to 1600 mg to normal male subjects. Furegrelate produced a dose-related inhibition of thromboxane synthesis for 8-12 hours when measured either ex vivo from platelet-rich plasma (PRP) or in vivo from urine. In general, the extent of thromboxane synthesis inhibition was greater in PRP than in urine. Furegrelate significantly inhibited platelet aggregation, but the effect was variable and measurements of thromboxane synthase did not predict the impact on platelet aggregation. Bleeding times and coagulation parameters were not altered significantly. Furegrelate was well absorbed orally with Tmax = 1 hr and t1/2 = 3.5 to 5 hrs. There was no marked metabolism; elimination was primarily by renal excretion of parent compound. Thus, furegrelate is an effective inhibitor of thromboxane synthase in man with a relatively long biologic and circulating half-life.

Pharmacokinetics of furegrelate after oral administration to normal humans.

Furegrelate sodium is a thromboxane synthetase inhibitor with potential for the treatment of various diseases including hypertension, thrombosis, and renal disorders. The absorption and disposition of the parent drug in normal male volunteers have been studied after single- and multiple-dose oral administration. The results from the single-dose study indicate that furegrelate is rapidly absorbed, with a Tmax of 1.0-1.7 hr, has an apparent terminal disposition rate constant of 0.12-0.17 hr-1, and is eliminated primarily by the kidney, with 62-78% of the dose excreted as parent drug. After multiple-dose oral administration for 4.5 days using a b.i.d. dosing regimen, no apparent change in the absorption, disposition, and elimination kinetics is detected and only a slight potential for drug accumulation is observed.

Arylformamidines with antinociceptive properties.

A series of formamidines structurally related to clonidine were synthesized and investigated as potential nonopiate analgesics. Several of these compounds showed potent analgesic activity (ED50 on HCl writhing less than 1.0 mg/kg) with low potential for hypotensive effects. A qualitative description of the structure-activity relationship of this series reveals that the 2,4- and 2,6-dimethylphenyl compounds are more potent analgesics than are the corresponding dichlorophenyl compounds.

The analgesic activity of a clonidine analog. The formamidine, U-47,476A.

A compound structurally related to clonidine, N,N-dimethyl-N'-(2,4, 6-trimethyl phenyl)formamidine hydrochloride (U-47,476A), was evaluated for analgesic activity; it produced a significant analgesia in mice and rats in several analgesiometric procedures. The analgesic potency varied considerably with different analgesiometric tests, with ED50s ranging from 0.4 mg/kg for writhing in mice induced by hydrochloric acid to greater than 30 mg/kg for the tail-flick test in rats. Although the potency was less than that of clonidine, it was still in the range of pentazocine. Then U-47,476A was further examined to determine whether the analgesic effect was mediated by alpha-adrenergic mechanisms and accompanied by hypotension and sedation, similar to that produced by clonidine. The drug U-47,476A failed to lower significantly blood pressure in rats given 10 and 30 mg/kg subcutaneously, suggesting a possible separation of the hypotensive and analgesic properties of this compound. The locomotor activity of mice was unaltered after 0.5 mg/kg of U-47,476A; however, a significant decrease in activity was observed after the administration of 5 mg/kg. The effect of U-47,476A on locomotor activity in the mouse was significantly less than that for an approximately equipotent analgesic dose of clonidine. The analgesic effect of U-47,476A was antagonized by yohimbine, but not by reserpine, naloxone or phentolamine, Thus, the attenuation of the response to noxious stimuli by U-47,476A is mediated by alpha 2-adrenoceptors and not by opioid receptors or presynaptic monoaminergic mechanisms, similar to clonidine-induced analgesia.

A multiclinic, placebo-controlled, double-blind study of prostaglandin E1 in Raynaud's syndrome.

Prostaglandin E1 (alprostadil, Prostin VR Sterile Solution, PGE1) was evaluated in patients with Raynaud's syndrome in a multiclinic, placebo-controlled, double-blind study. A total of 55 patients with either primary Raynaud's disease or Raynaud's disease secondary to systemic sclerosis were randomly assigned to receive either PGE1 administered intravenously at 10 ng/kg/min for 72 hours or placebo administered in the same manner. The frequency and severity of Raynaud's attacks were then monitored for up to four weeks by use of in-clinic questionnaires and patients' daily diaries. Haemodynamic assessments included measurements of skin temperature and the finger systolic pressure response to localised digital cooling. Immediately after the infusion the overall symptoms in both the PGE1 and the placebo group showed marked improvement; by four weeks after infusion, in some cases, values had not returned to pretreatment levels. There was, however, no marked benefit of PGE1 treatment over that of placebo. Although PGE1 significantly increased skin temperature during and immediately after infusion, the effect did not persist at two- and four-week follow-up evaluations. The finger systolic pressure response to localised digital cooling (15 degrees C) increased more in the PGE1-treated group than in the placebo-treated group, but the difference was not statistically significant. There was no difference in ulcer healing between the two treatment groups. These results failed to substantiate earlier open-label reports that a 72-hour intravenous infusion of PGE1 in patients with Raynaud's syndrome produced significant clinical benefit.

Alteration of shock titration thresholds in the cat following intrathecal substance P administration.

Substance P (SP) was injected intrathecally (10 or 100 micrograms) into cats previously implanted with nerve-stimulating electrodes and the effect on shock titration thresholds was evaluated. Elevated shock thresholds were observed in 5 of 8 cats following the 100 micrograms dose of SP. In addition, one cat exhibited a decreased threshold and two cats showed a triphasic (increase, decrease, increase) response. Overt behavioral effects of intrathecal SP were mild, but suggested that injection of the drug was aversive.

Lateral reticular formation as a site for morphine- and clonidine-induced hypotension.

The possible role of the lateral reticular formation (LRF) in morphine-induced hypotension was investigated. Morphine (5-10 micrograms) microinjected into 15 of 25 sites in the LRF of anesthetized cats reduced mean (+/- S.E.) arterial pressure by 18.4 +/- 2.1 mmHg. Morphine applied microiontophoretically on LRF neurons had a predominately inhibitory effect on LRF cells, decreasing spontaneous rate in 51%. Since the LRF has been suggested as a site of action for clonidine-induced hypotension, clonidine was also applied microiontophoretically to these neurons. Of the cells evaluated, 43% were inhibited by clonidine. Individual cells typically responded in the same manner to morphine and clonidine. An inhibition of LRF cells by morphine and clonidine is consistent with their hypotensive action and the tonic vasopressive role assigned to the LRF. Collectively, these results suggest that the LRF is a site at which morphine and clonidine may produce their hypotensive effect.

Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease. Results of a prospective randomized, double-blind, multicenter clinical trial.

Most previous reports suggesting beneficial effects of prostaglandin E1 (PGE1) have been retrospective and uncontrolled. Therefore, this study was undertaken to assess the efficacy of PGE1 in the treatment of ischemic ulcers in patients with peripheral vascular occlusive disease (PVOD). One hundred twenty patients with one to three ischemic ulcers not healing for 3 weeks with standard care were randomized to receive either PGE1 (20 ng/kg/min) or a placebo for 72 hours through a central venous catheter. Ulcers were measured and photographed, and the rest pain was evaluated before and after infusion and at 1- and 2-month follow-up intervals. Fifty-seven patients with 95 ulcers received PGE1. Seventeen ulcers healed (18%); 22 ulcers decreased in size (23%); 37 ulcers remained unchanged or increased in size (39%); five new ulcers developed during the study (5%); and 14 ulcers had inadequate follow-up (15%). Sixty-three patients with 115 ulcers received a placebo. Nineteen ulcers healed (16%); 38 ulcers decreased in size (33%); 45 ulcers remained unchanged or increased in size (39%); three new ulcers developed during the study (3%); and 10 ulcers had inadequate follow-up (9%). None of the above differences between the drug-treated group and the placebo-treated group was statistically significant. This study did not demonstrate efficacy for intravenously administered PGE1 in the healing of ischemic ulcers in patients with PVOD.

An ultrasound-induced tail-flick procedure: evaluation of nonsteroidal antiinflammatory analgesics.

An ultrasonic stimulus was used to elicit a nociceptive response (tail-flick) in mice. Acetaminophen, flurbiprofen, indomethacin, and zomepirac all produced an attenuation in the tail-flick response in a dose-related manner (100-400 mg/kg p.o.). Aspirin failed to significantly alter ultrasound-induced tail-flick latencies until the dose was raised to 700 mg/kg. Morphine (10 mg/kg, s.c.) produced the greatest attenuation in the tail-flick response, whereas chlorpromazine (20 mg/kg, p.o.) had no effect. The results indicate that this procedure can be used to evaluate analgesic drugs.

Lesions in nucleus reticularis gigantocellularis: effect on the antinociception produced by micro-injection of morphine and focal electrical stimulation in the periaqueductal gray matter.

The effect of bilateral electrolytic lesions in the nucleus reticularis giganto-cellularis (NGC) on the antinociceptive efficacy of morphine and electrical stimulation applied in the periaqueductal central gray matter (PAG) was investigated. Antinociception, evaluated by standard hot plate and tail-flick analgesiometric tests, was reliably produced by morphine (5 microgram) and focal electrical stimulation (40-200 micro A) administered in the PAG of rats via chronic indwelling cannula/electrode assemblies. Subsequent to the initial antinociceptive testing, bilateral electrolytic lesions were introduced in the NGC and the antinociceptive efficacy of morphine and stimulation in the PAG was again evaluated. Lesions in the NGC prevented the expression of the antinociception produced by the microinjection of morphine in the PAG whereas the antinociception resulting from electrical stimulation in the PAG was unaffected. Further, lesions in the NGC did not alter baseline (control) nociceptive thresholds in either analgesiometric test. These results provide additional support for involvement of the NGC in morphine-induced antinociception and, in addition, suggest that the NGC is not essential to a tonically-active inhibitory system or to the antinociception produced by focal electrical stimulation in the PAG.

Effect of morphine administered in the periaqueductal gray and at the recording locus on nociresponsive neurons in the medullary reticular formation.

Neurons in the medullary reticular formation (MRF) contained within the nuclei reticularis gigantocellularis and reticularis paragigantocellularis were evaluated for their responses to morphine administered in the periaqueductal gray (PAG) and iontophoresed at the recording site. Morphine had a predominant excitatory effect on neurons in the MRF whether microinjected in the PAG or iontophoresed at the recording locus. Although morphine generally excited neurons in the MRF when administered at either site, examination of individual neurons for their responses to both modes of administration of morphine indicated that the effect produced by morphine administered in the PAG was rarely mimicked by morphine iontophoresed at the recording locus. Moreover, morphine administered in the PAG markedly attenuated the noxious evoked excitatory response of MRF neurons, an effect not reliably produced by morphine iontophoresed in the MRF when microinjected in the PAG is not mediated by an enkephalinergic interneurons. The implications of these results on the role of the MRF in opiate-induced antinociception are discussed.

Effects of focal electrical stimulation and morphine microinjection in the periaqueductal gray of the rat mesencephalon on neuronal activity in the medullary reticular formation.

Neurons in the medullary reticular formation (MRF; nucleus reticularis gigantocellularis and nucleus reticularis paragigantocellularis) were evaluated for their involvement in the analgesia produced by focal electrical stimulation and microinjection of morphine into the periaqueductal gray region (PAG) of the rat mesencephalon. Analgesia-producing PAG stimulation altered the spontaneous activity of 80% of the neurons in the MRF (both excitation and inhibition were observed) and inhibited the noxious-evoked excitation of 75% of MRF neurons. Microinjection of morphine into the PAG also increased (50%) and decreased (17%) the spontaneous activity of MRF units and inhibited the noxious-evoked excitation of 47% of MRF neurons. These effects were specific for analgesia produced by the PAG manipulations and were partially reversed by naloxone. The role of the MRF in PAG-induced analgesias and the degree of overlap in neuronal systems influenced by intracranial morphine and electrical stimulation is discussed.