Prevention of acute emesis in cancer patients following high-dose cisplatin with the combination of oral dolasetron and dexamethasone.

PURPOSE: Dolasetron is a 5-HT3 antagonist antiemetic with active oral and intravenous formulations. The effects of this class are enhanced when combined with dexamethasone. This study tested the ability of the combination of oral dolasetron 200 mg and oral dexamethasone 20 mg to prevent acute emesis in cancer patients receiving initial cisplatin at doses > or = 70 mg/m2. Additionally, patients were randomly assigned to receive a second dosage of the regimen 16 hours later to improve control of acute symptoms. PATIENTS AND METHODS: A total of 75 patients were entered, with 38 randomized to the two-dose regimen. Thirty-five percent were women and 77% had lung cancer. RESULTS: Overall, the regimen prevented acute vomiting in 76% (95% confidence interval, 65% to 85%), including 74% of 35 patients who received cisplatin at doses > or = 100 mg/m2. There was no observed difference in emesis prevention between the one-dose (76%) and two-dose (76%) regimens (95% confidence interval for the difference, -20% to 19%). The median time to the onset of emesis was 19 hours for the one-dose regimen and 17 hours for the two-dose regimen in those patients with emesis. Headache occurred in 11% who received one dose and 16% who received two doses. CONCLUSION: The combination of oral dolasetron 200 mg and dexamethasone 20 mg given only once prevented acute emesis in 76% of patients who received cisplatin > or = 70 mg/m2. Administration of a second dose of the regimen did not improve the observed prevention rate or delay the time to emesis. This one-dose oral regimen has comparable or better effectiveness than reported results of intravenous combination regimens in preventing cisplatin-induced vomiting and merits further study and use.

Effect of diltiazem and low-dose aspirin on platelet aggregation and ATP release induced by paired agonists.

The authors studied the effects of diltiazem, administered alone and together with low-dose aspirin, on the platelet response to paired agonists. After a baseline period, 25 healthy volunteers were given oral diltiazem for 1 week (120, 240, or 360 mg/day), and then crossed over randomly between 1 week on diltiazem plus aspirin (81 mg/day), and 1 week on aspirin (81 mg/day) alone. Platelet function was tested on 2 consecutive days in each period. Synergistic platelet aggregation and ATP release were obtained at baseline using a subthreshold concentration of arachidonic acid combined with platelet activating factor, ADP, or epinephrine. Diltiazem resulted in significant decrease from baseline in platelet aggregation and ATP release using the arachidonic acid-epinephrine combination (35% and 40% decrease, respectively, p < 0.01) and a significant decrease in aggregation using the arachidonic acid-ADP combination (22% decrease, p < 0.01). The effects were neither dose-related, nor accompanied by any significant change in serum thromboxane B2 levels or bleeding times. There was no significant difference between the effects of aspirin alone and aspirin plus diltiazem on the synergistic platelet aggregation and ATP release induced by the paired agonists, or on thromboxane B2 levels or bleeding times. Diltiazem administered in vivo partially inhibits the synergistic platelet aggregation and ATP release induced by paired agonists; however, in contrast to a previous in vitro study it does not potentiate the platelet-inhibitory effect of aspirin.

Controlled studies of the efficacy and safety of combined probucol-colestipol therapy.

A comprehensive clinical evaluation of the effects of combined probucol-colestipol therapy was undertaken in 71 hypercholesterolemic patients. In the first 18-month double-blind, double-placebo, crossover study, the effects of 1 g/day of probucol and 20 g/day of colestipol were compared with the drugs used singly in 47 patients. The combination decreased low density lipoprotein (LDL) cholesterol from a diet-placebo baseline of 242 +/- 51 mg/dl to 171 +/- 41 mg/dl. LDL cholesterol levels were decreased by more than 30% in 49% of patients, and by more than 40% in 17% of patients. Combined drug use eliminated the gastrointestinal side effects of single-drug administration or diminished their severity. Twenty-two patients who complained of resin-induced constipation entered a 19-month continuation trial that called for a half-dose of colestipol during combination treatment. This therapy decreased the LDL baseline level of 239 +/- 46 mg/dl by more than 25% in 41% of patients, and by more than 45% in 9% of patients. All patients were able to tolerate the modified probucol-colestipol therapy. Finally, a comparison was made between the hypocholesterolemic effects of combined probucol-colestipol therapy obtained after 1 and 3 years in 24 patients. These were sustained in all but 5 patients. Combined probucol-colestipol therapy increases the hypocholesterolemic effects and decreases the gastrointestinal side effects of either drug used alone. In patients who cannot tolerate full doses of resin, a half-dose may render the drug more acceptable without diminishing its lipid-lowering effect.

Low- vs high-dose aspirin. Effects on platelet function in hyperlipoproteinemic and normal subjects.

Low-dose aspirin may be inadequate for inhibition of platelet function in hyperlipoproteinemics due to increased platelet reactivity. Platelet function was studied in 18 type II hyperlipoproteinemic and 12 normal subjects after at least ten days of treatment with placebo and with low-dose (0.45 mg/kg/day) and high-dose (900 mg/day) aspirin. In the normal and hyperlipoproteinemic subjects, low-dose aspirin produced near maximal (90%) inhibition of platelet thromboxane generation, significant prolongation of the bleeding time, and significant inhibition of platelet aggregation, similar in degree to the inhibition produced by high-dose aspirin. There was no significant difference between hyperlipoproteinemic and normal subjects in any of the platelet function measures before and after aspirin treatment. Thus, a daily 0.45-mg/kg aspirin dose (20 to 45 mg) effectively inhibited platelet function in type II hyperlipoproteinemics, who do not appear to have an increased dose requirement for aspirin.

Platelet function in hypercholesterolemics before and after hypolipidemic drug therapy.

Platelet function parameters were studied in type II hyperlipoproteinemics in relation to baseline and drug-induced changes in serum cholesterol levels. There were no significant differences between 28 type II hyperlipoproteinemics and 19 normal subjects in baseline values for platelet aggregation, thromboxane generation, sensitivity to prostacyclin, plasma platelet factor 4 or beta-thromboglobulin. Eleven of the hyperlipoproteinemic patients were treated with a combination of the cholesterol-lowering drugs probucol and colestipol. The drug treatment resulted in statistically significant lowering of serum total and low-density lipoprotein (LDL)-cholesterol levels (30% reduction of mean LDL-cholesterol, p less than 0.01); however, there was no significant change in any of the platelet function parameters after the drug treatment compared with placebo. These results provide evidence against a relationship between serum cholesterol levels and in vitro platelet function.

Low-dose colestipol plus probucol for hypercholesterolemia.

The hypocholesterolemic and adverse effects of colestipol, 20 g/day, and colestipol, 10 g/day combined with probucol, 1 g/day, were compared. A double-placebo, diet-controlled, crossover trial that lasted 19 months was undertaken on 22 hypercholesterolemic patients who had low-density lipoprotein (LDL) cholesterol levels greater than 180 mg/dl after 3 months of diet and placebo treatment. Uniformity of diet and physical activity were monitored throughout the study. Compared with baseline values after 3 months on diet-placebo treatment, "combined" therapy reduced LDL cholesterol by more than 20% in 15 patients, more than 25% in 9 patients and more than 45% in 2 patients. Treatment with "half-dose" colestipol and probucol resulted in the greatest mean LDL cholesterol reduction, from 239 mg/dl during diet-placebo period to 170 mg/dl; the difference was not statistically significantly different from the reduction to 180 mg/dl with 20 g of colestipol alone. Fifteen patients showed the greatest reduction in LDL cholesterol after combined therapy. Probucol produced statistically significant reductions in very low density lipoprotein and high-density lipoprotein cholesterol. The major gastrointestinal side effects of single therapy with colestipol (constipation) and probucol (diarrhea) were ameliorated or abolished by concomitant administration. Probucol-colestipol co-administration allowed a 50% reduction in the colestipol dosage, with similar efficacy and improved tolerability and reduced mean serum LDL cholesterol with a frequency and magnitude rarely seen with other hypocholesterolemic treatments. Hypercholesterolemic persons who cannot tolerate full doses of resins may receive equal benefit by half the dose if probucol is added to the regimen.

Cadmium-binding proteins of rat testes. Characterization of a low-molecular-mass protein that lacks identity with metallothionein.

Cadmium-binding proteins in the cytosol of testes from untreated rats were separated by Sephadex G-75 gel filtration. Three major testicular metal-binding proteins (TMBP), or groups of proteins, with relative elution volumes of approx. 1.0 (TMBP-1), 1.7 (TMBP-2) and 2.4 (TMBP-3) were separated. Elution of Zn-binding proteins exhibited a similar pattern. TMBP-3 has previously been thought to be metallothionein (MT), and hence this protein was further characterized and compared with hepatic MT isolated from Cd-treated rats. Estimation of Mr by gel filtration indicated a slight difference between MT (Mr 10000) and TMBP-3 (Mr 8000). Two major forms of MT (MT-I and MT-II) and TMBP-3 (TMBP-3 form I and TMBP-3 form II) were obtained after DEAE-Sephadex A-25 anion-exchange chromatography, with the corresponding subfractions being eluted at similar conductances. Non-denaturing polyacrylamide-gel electrophoresis on 7% acrylamide gels indicated that the subfractions of TMBP-3 had similar mobilities to those of the corresponding subfractions of MT. However, SDS (sodium dodecyl sulphate)/12% (w/v)-polyacrylamide-gel electrophoresis resulted in marked differences in migration of the two corresponding forms of MT and TMBP-3. Co-electrophoresis of MT-II and TMBP-3 form II by SDS/polyacrylamide-gel electrophoresis revealed two distinct proteins. Amino acid analysis indicated much lower content of cysteine in the testicular than in the hepatic proteins. TMBP-3 also contained significant amounts of tyrosine, phenylalanine and histidine, whereas MT did not. U.v.-spectral analysis of TMBP-3 showed a much lower A250/A280 ratio than for MT. Thus this major metal-binding protein in testes, which has been assumed to be MT is, in fact, a quite different protein.

Cadmium-binding proteins of rat testes. Apparent source of the protein of low molecular mass.

Fractionation of rat testicular cytosolic proteins by gel filtration indicates three major metal-binding proteins, or groups of proteins, termed testicular metal-binding protein (TMBP) 1, 2 and 3 by order of elution. The major heat-stable, metal-binding proteins in testes is TMBP-2, which has an Mr of approx. 25000. In most tissues, metallothionein (MT) is the major heat-stable, metal-binding protein, but it has an Mr of 6000. This testicular protein (TMBP-2) is much larger than MT, and since polymeric forms of MT have been previously reported, further characterization of TMBP-2 was performed. TMBP-2 was separated into two forms by DEAE-Sephadex A-25 anion-exchange chromatography. Amino acid analysis of both forms of TMBP-2 revealed that they differed markedly from MT, having particularly low cysteine contents. However, amino acid analysis showed that TBMP-2 was strikingly similar to TMBP-3, with an approximate stoichiometric relationship of 4:1. Therefore, experiments were conducted to determine if TMBP-3 could be a breakdown product of TMBP-2. Heat treatment of testicular cytosol in room air before gel filtration resulted in a marked increase in TMBP-3 and loss of TMBP-2. Storing intact testes at -20 degrees C for 2 weeks before processing for gel filtration also resulted in an increase in TMBP-3 and a loss of TMBP-2. Addition of a reducing agent (dithiothreitol) or proteinase inhibitor (N-ethylmaleimide) in processing of samples before gel filtration inhibited the appearance of TMBP-3. Results suggest that the low-Mr Cd-binding protein (TMBP-3) of rat testes results from either proteolytic or oxidative breakdown of a higher-Mr species, or from a combination of such factors.

Probucol with colestipol in the treatment of hypercholesterolemia.

The effects of therapy with 1 g of probucol and 20 g of colestipol were compared with those of the drugs used singly on 47 patients with hypercholesterolemia in a double-blind, double-placebo, diet-controlled, crossover trial that lasted 18 months. The probucol and colestipol combination, but neither drug alone, reduced mean serum low-density-lipoprotein (LDL)-cholesterol levels from 242 +/- 51 (SE) mg/dL during the diet and placebo phase to 171 +/- 41 mg/dL. Probucol significantly lowered high-density-lipoprotein (HDL)-cholesterol levels and increased LDL:HDL-cholesterol ratios. Combination therapy did not change LDL:HDL cholesterol ratios. Probucol alone or in combination reduced very-low-density-lipoprotein cholesterol levels, despite concomitant elevations of serum triglyceride levels caused by colestipol in the combination protocol. Gastrointestinal side effects of single drugs were abolished when drugs were used in combination. Compared with the values in the diet-placebo phase, LDL-cholesterol levels were reduced by more than 20% in 81% of patients, by more than 30% in 49%, and by more than 40% in 17%. This drug combination proved to be safer and have greater hypocholesterolemic effects in more patients than other marketed drug treatments.

Electrocardiographic effects of probucol. A controlled prospective clinical trial.

Probucol is known to prolong QT intervals in some patients and to produce fatal arrhythmias in selected animal species. To assess the prevalence and clinical relevance of this effect in a controlled manner, we analyzed electrocardiograms (ECGs) and medical events in patients during a placebo-controlled crossover trial comparing single or combined administration of probucol and colestipol. Forty-two Type II hyperlipoproteinemic patients were studied for eighteen to twenty-four months. Two cardiologists independently read the tracings which were previously arranged randomly without names or dates. There were no statistical differences between the reports of the ECG parameters by the two cardiologists. The mean QTc interval of the entire patient population was lengthened after probucol administration without reaching statistical significance when compared to placebos or colestipol treatments. Forty-eight % of the patients showed lengthening of the QTc interval during probucol treatment by 11 to 70 msec increment over baseline placebo. The remaining had either no change or shortening of the interval. There were no statistically significant differences in means of R-R, PR, QRS, QTc or QoT intervals among placebo, probucol., colestipol and probucol plus colestipol treatments. It is concluded that probucol prolonged QT intervals in the electrocardiograms of about one half of patients receiving the drug with no other clinical or statistically significant evidence of cardiotoxicity or electrocardiographic effects.

Differences in iodinated peptides and thyroid hormone formation after chemical and thyroid peroxidase-catalyzed iodination of human thyroglobulin.

The distribution of iodine among the polypeptides of human goiter thyroglobulin (Tg) was examined. Tg was iodinated in vitro with 131I to levels of 2 to 84 gram atoms (g.a.)/mol using thyroid peroxidase (TPO) or a chemical iodination system. The samples were reduced, alkylated, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two low-molecular-weight peptides appeared preferentially in radioautograms of the sodium dodecyl sulfate (SDS) gels of TPO-iodinated samples. Iodination of these peptides increased sharply in the TPO-treated Tg as the level of total iodine/molecule rose. Radioiodine was incorporated into these same gel regions in the chemically treated Tg, but only after much higher levels of total iodination were reached. Differences in iodoamino acid distribution were also noted between the chemically and enzymatically iodinated thyroglobulins. In the chemically iodinated samples, little thyroxine (T4) was synthesized, even at high iodine levels. In the TPO-treated samples only small amounts of T4 were seen below 14 g.a. total I/mol, while at or above that level of iodination T4 formation increased sharply. To examine the coupling process, Tg was chemically iodinated, excess I- removed, and the samples treated with TPO and a H2O2-generating system in the absence of iodide. Radioautograms obtained from SDS-polyacrylamide gels of reduced and alkylated protein from such coupling assays showed an increase in the level of iodine in the low-molecular-weight peptides after TPO treatment. Thyroxine production also increased with TPO treatment. The addition of free DIT (a known coupling enhancer) to the [131I]Tg/TPO incubation increased both the production of T4 and the amount of iodine in the smaller polypeptides. Two-dimensional maps prepared from CNBr-digested TG showed differences between the coupled and uncoupled samples. Our observations confirm the importance of the low-molecular-weight peptides derived from Tg in thyroid hormone synthesis. At total iodine levels above 14 g.a./mol Tg in enzymatically treated samples there is selective incorporation of iodine into both the low-molecular-weight polypeptides and into thyroid hormone.

Thyroglobulin structure-function. The amino acid sequence surrounding thyroxine.

A 19-residue, thyroxine (T4)-containing peptide, Tryp-T4, has been isolated from the tryptic digest of a low molecular weight, iodine-enriched fragment derived from 19S bovine thyroglobulin. This tryptic peptide represents the only site of significant iodination in the parent polypeptide fragment. The amino acid sequence of the tryptic peptide has been determined and is NH2-Asn-Ile-Phe-Glu-T4-Gln-Val-Asp-Ala-Gln-Pro-Leu-Arg-Pro-Cys-Glu-Leu-Gln- Arg-COOH. The carboxyl-terminal sequence of this peptide shows a high probability of a beta-turn. These findings establish the involvement of at least a single unique sequence within thyroglobulin in thyroxine biosynthesis and the general nature of a hormonogenic site within this protein. This sequence contains at least 30% of the thyroxine present in 19 S bovine thyroglobulin.