3,5-Dimethyl-4-isoxazoyl selenocyanate as promising agent for the treatment of Leishmania infantum-infected mice.

Compounds 1 and 2 (selenocyanate and diselenide derivatives, respectively) were evaluated for their potential use in vivo against visceral leishmaniasis (VL). Both entities showed low cytoxicity in vitro in Vero and Caco-2 cell lines. However, the compounds were not suitable for their oral administration, since they exhibited poor values of intestinal permeability in vitro. Microsomal stability assays did not show any metabolite for compound 1 after 120 min, whereas 2 was highly metabolized by the enzyme CYP450. Thus, the in vivo efficacy of compound 1 was assessed in a murine model of L. infantum VL. The daily i.v. administration of 1 mg/kg of compound 1 during 5 consecutive days reduced parasite load in liver, spleen and bone marrow (99.2%, 91.7% and 61.4%, respectively) compared to non-treated mice. To the best of our knowledge, this is the first time that a selenium compound has been tested in vivo against VL. Thus, this work evidences the possible usefulness of selenocyanate derivatives for the treatment of this disease.

Aurocyanide, dicyano-aurate (I), a pharmacologically active metabolite of medicinal gold complexes.

The aurocyanide anion, Au(CN) (2) (-) , is a human metabolite of several anti-rheumatic gold complexes containing monovalent gold (I) bound to a sulphur ligand. This article reviews some of the chemical and pharmacological properties of this intriguing metabolite, and reports its anti-arthritic and anti-inflammatory activity in rats. Au(CN) (2) (-) is generated from the therapeutic gold complexes by small amounts of hydrogen cyanide, HCN, produced from thiocyanate, SCN(-), by myeloperoxidase (MPO) an enzyme in neutrophils which normally produces hypochlorite, OCl(-). Thus, Au(CN) (2) (-) is formed at sites of inflammation where activated neutrophils are present. This includes atherosclerotic lesions as well as inflamed joints. MPO also oxidises Au(CN) (2) (-) to Au(III) complexes such as Au(CN) (4) (-) .Au(CN) (2) (-) is normally a very stable monovalent gold complex. In a biological context, only low concentrations are ever present at both extracellular and intracellular sites. However, Au(CN) (2) (-) produced locally may facilitate the cellular uptake and hence the therapeutic and toxic effects of gold drugs. Au(CN) (2) (-) may also be involved in a redox cycle where Au(CN) (2) (-) is oxidised to Au(CN) (4) (-) which is, in turn, reduced back to Au(CN) (2) (-) by endogenous thiols. There are still many questions to be resolved concerning Au(CN) (2) (-) including its intrinsic toxicity and the extent to which it may contribute to the overall anti-arthritic activities of the gold-thiolates from which it is formed in vivo.

Preparation and surface characterization of HMDI-activated 316L stainless steel for coronary artery stents.

Poor compatibility between blood and metallic coronary artery stents is one reason for arterial restenosis. Immobilization of anticoagulant agents on the stent's surface is feasible for improving compatibility. We examined possible surface-coupling agents for anticoagulant agent immobilization. Hexamethylene diisocyanate (HMDI) and 3-aminopropyl-triethoxysilane (APTS) were examined as surface-coupling agents to activate 316L stainless steel (e.g., stent material). The activated surface was characterized using Fourier transformation infrared spectroscopy (FTIR), atomic force microscope (AFM), surface plasmon resonance (SPR), and trinitrobenzene sulfonic acid (TNBS) assay. In FTIR analysis, HMDI and APTS were both covalently linked to 316L stainless steel. In AFM analysis, it was found that the HMDI-activated surface was smoother than the APTS-activated one. In SPR test, the shift of SPR angle for the APTS-activated surface was much higher than that for the HMDI-activated surface after being challenged with acidic solution. TNBS assay was used to determine the amount of immobilized primary amine groups. The HMDI-activated surface was found to consist of about 1.32 micromol/cm(2) amine group, whereas the APTS-activated surface consisted of only 0.89 micromol/cm(2) amine group. We conclude that the HMDI-activated surface has more desirable surface characteristics than the APTS-activated surface has, such as chemical stability and the amount of active amine groups.

Evaluation of benzyl selenocyanate glutathione conjugate for potential chemopreventive properties in colon carcinogenesis.

Observational, clinical and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. Since toxicity and chemopreventive efficacy of selenium compounds depend to a large extent, on the form of selenium the development of efficacious organoselenium compounds with low toxicity is being pursued in our laboratory. We have assessed the chemopreventive properties of a newly synthesized organoselenium compound, benzyl selenocyanate glutathione conjugate (BSeSG), and of benzyl selenocyanate (BSC), as a positive control, using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 10 or 20 ppm BSeSG (1.7 and 3.4 ppm as Se, respectively), or 10 ppm BSC (4.1 ppm as Se). One week later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg of body weight, once weekly for 2 weeks). All animals were sacrificed 7 weeks after the last AOM injection, and the ACF, levels of prostaglandin E2 (PGE2), cyclooxygenase protein expression (COX-1 and -2), and glutathione S-transferase type mu (GST-mu) were determined in the colon. As expected, dietary administration of BSC suppressed ACF development by about 37%. In rats administered 10 or 20 ppm BSeSG, the frequencies of AOM-induced colonic ACF were significantly decreased compared to those of rats given AOM and control diet by about 41% (P<0.01) and 61% (P<0.001), respectively. Administration of BSeSG inhibited PGE2 production (81-88% inhibition) via COX-2 synthesis in the colonic mucosa (18-60% inhibition). Also, BSeSG increased GST-mu protein activity in colonic mucosa (30-32% increase). These data suggest that a newly synthesized organoselenium compound, BSeSG might be a promising chemopreventive agent against colon carcinogenesis.

Hemifacial spasm caused by vascular compression of the distal portion of the facial nerve. Report of seven cases.

It is generally accepted that hemifacial spasm (HFS) and trigeminal neuralgia are caused by compression of the facial nerve (seventh cranial nerve) or the trigeminal nerve (fifth cranial nerve) at the nerve's root exit (or entry) zone (REZ); thus, neurosurgeons generally perform neurovascular decompression at the REZ. Neurosurgeons tend to ignore vascular compression at distal portions of the seventh cranial nerve, even when found incidentally while performing neurovascular decompression at the REZ of that nerve, because compression of distal portions of the seventh cranial nerve has not been regarded as a cause of HFS. Recently the authors treated seven cases of HFS in which compression of the distal portion of the seventh cranial nerve produced symptoms. The anterior inferior cerebellar artery (AICA) was the offending vessel in five of these cases. Great care must be taken not to stretch the internal auditory arteries during manipulation of the AICA because these small arteries are quite vulnerable to surgical manipulation and the patient may experience hearing loss postoperatively. It must be kept in mind that compression of distal portions of the seventh cranial nerve may be responsible for HFS in cases in which neurovascular compression at the REZ is not confirmed intraoperatively and in cases in which neurovascular decompression at the nerve's REZ does not cure HFS. Surgical procedures for decompression of the distal portion of the seventh cranial nerve as well as decompression at the REZ should be performed when a deep vascular groove is noticed at the distal site of compression of the nerve.

Chemoprevention of colon cancer by organoselenium compounds and impact of high- or low-fat diets.

BACKGROUND: Observational and experimental studies have suggested that dietary supplementation with selenium can inhibit the development of colon cancer. However, many forms of selenium are toxic. Consequently, the development of efficacious compounds with low toxicity has been pursued. PURPOSE: Two synthetic organoselenium compounds, p-methoxy-benzyl selenocyanate (p-methoxy-BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC), were tested for their ability to inhibit colon carcinogenesis in rats that were treated with the carcinogen azoxymethane and fed low- or high-fat diets. METHODS: Groups of 5-week-old male F344 rats (42 animals/ group) were fed either a high-fat diet or a low-fat diet with or without added p-methoxy-BSC (10 or 20 parts per million [ppm]) or p-XSC (20 ppm). Two weeks later, 30 animals in each group received a subcutaneous injection of azoxymethane (15 mg/kg body weight); 1 week later, they received a second injection. The remaining 12 rats in each group received two injections of saline. Three days after the second injection of carcinogen or saline, animals being fed diets with p-methoxy-BSC or p-XSC were switched to corresponding organoselenium-free low- or high-fat diets for the remainder of the study to determine the effects of the selenium compounds on the initiation phase of colon carcinogenesis. At that time, groups of animals that had been maintained on organoselenium-free low- or high-fat diets were switched to diets containing p-methoxy-BSC or p-XSC until the end of the study to determine the effects of these compounds on the postinitiation phase of colon carcinogenesis. All animals were killed during the 38th week after azoxymethane or saline treatment, and histopathologic analysis of the colon tumors was performed. Colon tumor incidence and multiplicity were analyzed statistically. RESULTS: No obvious toxic effects were observed following dietary administration of 10 or 20 ppmp-methoxy-BSC or 20 ppm p-XSC. Administration of 20 ppm p-methoxy-BSC in a high-fat diet during the initiation and postinitiation phases of colon carcinogenesis significantly (statistically) reduced colon tumor incidence; 10 ppmp-methoxy-BSC in a high-fat diet significantly reduced colon tumor incidence but only when it was given during the postinitiation phase. Colon tumor incidence was also significantly reduced when 20 ppm p-XSC was given in a high-fat diet during the initiation phase of colon carcinogenesis. When 20 ppm p-XSC was administered in either a high-fat diet or a low-fat diet during the postinitiation phase, both colon tumor incidence and multiplicity were significantly reduced; the greatest reductions were in animals fed a low-fat diet. CONCLUSIONS: In this model system, p-methoxy-BSC and p-XSC are effective agents for the chemoprevention of colon cancer. The effects of p-XSC were enhanced in animals fed a low-fat diet.

Evaluation of organoselenium compounds for potential chemopreventive properties in colon cancer.

Our previous studies have demonstrated that dietary benzylselenocyanate (BSC) and 1,4-phenylenebis (methylene) selenocyanate (p-XSC); organoselenium compounds, act as potential chemopreventive agents in colon carcinogenesis in F344 rats. As a part of a program aimed to develop less toxic and more effective chemopreventive organoselenium compounds than inorganic selenium and BSC, we evaluated the positional isomers of BSC namely o-, m-, and p-methoxy BSC and dibenzyl diselenide (DDS) for their potential chemopreventive properties using colonic epithelial cell proliferation as an efficacy endpoint. p-XSC and inorganic selenium, which were found to inhibit colon carcinogenesis in earlier preclinical efficacy study, were included as positive controls. Male F344 rats were fed the control diet containing 8 ppm Na2SeO3 or 10 ppm of each o-, m-, and p-methoxy BSC and DDS equivalent to 4.1 ppm Se or 20 ppm p-XSC (10 ppm Se) 2 weeks prior to carcinogen (AOM, 15 mg/kg body wt., once weekly for 2 weeks) administration and during and until 8 weeks after AOM treatment. Vehicle-control animals received an equal volume of normal saline. One hour prior to sacrifice, all animals were injected with bromodeoxyuridine (BrdU, 20 mg/kg body wt.). Administration of o-, m-, and p-methoxy BSC, p-XSC, DDS, and Na2SeO3 resulted in decreased colonic labeling index in animal treated with AOM compared to control diet. Notably, p-XSC and Na2SeO3, which showed previously colon tumor inhibitory activity in preclinical efficacy study, were also effective in the present study. The results of our previous and current studies indicate that structurally modified synthetic organoselenium compounds may have great potential as chemopreventive agents.

Sodium cyanate: from a promising therapeutic agent to a research tool in high altitude physiology.

Sodium cyanate (NaOCN) first appeared on the biomedical scene as a potential therapeutic agent for sickle-cell disease. Although it did not fulfill its early promise in the clinic, it proved to be useful as a pharmacological tool in physiological research, particularly in the physiology of oxygen transport. NaOCN has been especially valuable in the area of investigation which is reviewed here: the study of oxygen transport, both in normoxic and in hypoxic conditions, in experimental models in which NaOCN was used to induce a shift to the left of the oxygen dissociation curve. The classical idea is that a low Hb-O2 affinity is of adaptive value for life at high altitudes but it has been challenged by several pieces of evidence. One of them is the demonstration of increased survival in hypoxic hypoxia of animals with a high Hb-O2 affinity induced by NaOCN. We also discuss the advantages and potentially confounding factors which should be taken into consideration when interpreting results of studies in which the oxygen dissociation curve has been modified by administration of NaOCN.

Sodium cyanate: from a promising therapeutic agent to a research tool in high altitude physiology

Sodium cyanate (NaOCN) first appeared on the biomedical scene as a potential therapeutic agent for sickle-cell disease. Although it did not fulfill its early promise in the clinic, it proved to be useful as a pharmacological tool in physiological research, particularly in the physiology of oxygen transport. NaOCN has been especially valuable in the area of investigation which is reviewed here: the study of oxygen transport, both in normoxic and in hypoxic conditions, in experimental models in which NaOCN was used to induce a shift to the left of the oxygen dissociation curve. The classical idea is that a low Hb-O2 affinity is of adaptive value for life at high altitudes but it has been challenged by several pieces of evidence. One of them is the demonstration of increased survival in hypoxic hypoxia of animals with a high Hb-O2 affinity induced by NaOCN. We also discuss the advantages and potentially confounding factors which should be taken into consideration when interpreting results of studies in which the oxygen dissociation curve has been modified by administration of NaOCN

Cancer chemoprevention by aliphatic selenocyanates: effect of chain length on inhibition of mammary tumors and DMBA adducts.

The objective of this study was to examine the anticarcinogenic activity of a series of aliphatic selenocyanates with increasing length of the carbon side chain, CH3-(CH2)n-SeCN, in which n = 0, 2, 4 or 6. Their ability to prevent mammary cancer was evaluated during the initiation phase using the rat 7,12-dimethyl-benz[a]anthracene (DMBA) model. Each compound was added to the diet at a final concentration of 2 p.p.m. Se and was given from 2 weeks before to 1 week after DMBA administration. Analysis of the tumor data suggested the following order of chemopreventive potency for this series of aliphatic selenocyanates: heptyl approximately pentyl > propyl > methyl. Thus it appears that the length of the carbon side chain is a determinant in modulating the efficacy of these selenium homologs. In vivo results of total DMBA binding and adduct formation in the mammary cells showed a similar trend of progressive reductions following treatment by selenocyanates with increasing length of the alkyl side chain. These studies strongly indicate that aliphatic selenocyanates are effective blocking agents in the DMBA model and are capable of modulating events in the initiation phase of mammary carcinogenesis.

Comparative effect of inorganic and organic selenocyanate derivatives in mammary cancer chemoprevention.

Recently El-Bayoumy and coworkers have reported that 1,4-phenylene-bis(methylene)selenocyanate (p-XSC) was very effective in inhibiting 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis and adduct formation during the initiation phase (Cancer Res., 52, 2402-2407, 1992). Furthermore, this compound was found to be well tolerated by rats at high doses. The present study was designed to extend these earlier observations by investigating the response to lower levels of p-XSC given either before or after DMBA administration. At a level of 15 p.p.m. Se, p-XSC suppressed total mammary tumor yield by 80% and 52% in the initiation phase and post-initiation phase, respectively. A dose-response effect was evident in the range 5-15 p.p.m. Se. When p-XSC was given at a level of 5 p.p.m. Se during the entire course of the experimental period, total tumor yield was reduced by half. This dose is about 4 x less than the maximum tolerable dose (MTD). Other selenocyanate analogs were also examined in an attempt to obtain information on their respective chemopreventive index, which is calculated as the ratio of MTD to the effective dose which produces approximately a 50% inhibition in total tumor yield (ED50). The reagents studied included potassium selenocyanate, methyl selenocyanate and benzyl selenocyanate, as well as sodium selenite (reference compound). Compared to p-XSC, which has a chemopreventive index of 4.0, the other four compounds have a lower index ranging from 1.3 for sodium selenite and potassium selenocyanate to 2.0 for methyl selenocyanate and 2.5 for benzyl selenocyanate. A high chemopreventive index signifies that a compound is well tolerated at doses required for cancer suppression. The last component of the present study involved the repletion assay of liver glutathione peroxidase in selenium-deficient rats as a biomarker to estimate the metabolizability of the above selenium compounds. The bioavailability data suggest that the selenium from p-XSC is not as efficiently incorporated into glutathione peroxidase as the selenium from selenite or the other selenocyanate analogs. Currently, we are working under the hypothesis that the chemical structure of the RSeCN compound could affect activity per se and also influence the rate of release of selenium from the parent compound, thereby impacting on the anticarcinogenic efficacy, tolerance and bioavailability of the compound.

Alteration of the systemic antitumor activity of melphalan by sodium cyanate in MOPC-460D myeloma-bearing BALB/c mice.

Sodium cyanate is a selective inhibitor of protein synthesis in a variety of mammalian tumor cells without a corresponding effect on normal tissue of the tumor-bearing animals. In the present study, we investigated the potential role of sodium cyanate in the augmentation of the antitumor activity of melphalan in MOPC-460D myeloma-bearing BALB/c mice. The simultaneous intraperitoneal injection of sodium cyanate, 250 mg/kg, and melphalan, 12 mg/kg, followed by another dose of sodium cyanate, 200 mg/kg, administered 18 hours later, resulted in a tumor growth inhibition index (TGII) of 207%. In contrast, melphalan or sodium cyanate administered separately at the same dose induced a TGII of 133% and 15%, respectively, when compared to control animals. Furthermore, a direct comparison of the volume of tumor implants in mice treated with the combination of sodium cyanate and melphalan vs. those treated with melphalan alone showed a statistically significant growth inhibition in favor of the sodium cyanate and melphalan combination on days 35, 39, and 42 from initiation of treatment. The data presented here suggest that the antitumor activity of melphalan could be increased, with moderate toxicity, by the concomitant intraperitoneal administration of sodium cyanate in BALB/c mice bearing measurable subcutaneous MOPC-460D tumor transplants. This is the first report of an increase in melphalan antitumor activity by sodium cyanate at a tumor location distant from the site of injection.

Boron neutron capture therapy: linkage of a boronated macromolecule to monoclonal antibodies directed against tumor-associated antigens.

Two new protein-binding polyhedral boron derivatives, isocyanatoundecahydro-closo-dodecaborate(2-) (1) and isocyanato(trimethylamino)octahydro-closo-decaborate(1 -) (2), were synthesized. These anionic isocyanates have long hydrolysis half-lives at pH 7 and react readily with primary or secondary aliphatic amines resulting in spontaneous urea linkage. Utilizing 1, 1100 boron atoms (7.3% boron by weight) were incorporated per molecule of a polyclonal antibody directed against human thymocytes (anti-thymocyte globulin) without denaturation. However, immunoreactivity of the conjugates was lost. Reaction of 1 and 2 with polylysine yielded boronated macromolecules containing 21-28% boron by weight (up to 2000 boron atoms per molecule). Polylysine boronated with 2 was successfully linked to antibody molecules employing the heterobifunctional linking molecules N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) and m-maleimidobenzoyl sulfosuccinimide ester (sulfo-MBS). Separation of the conjugated antibody from the free boronated macromolecules and unconjugated antibody molecules has been achieved by gel filtration on a Sephacryl S-300 column. By linking boronated polylysine to antibodies, greater than 10(3) boron atoms were incorporated with the attachment of this species to one or more sites on the antibody molecule. The resulting immunoconjugates contained greater than 10(3) boron atoms per molecule, retained their immunoreactivity, and potentially might be useful for the selective delivery of large numbers of boron atoms to tumor cells.

Inhibition by dietary benzylselenocyanate of hepatocarcinogenesis induced by azoxymethane in Fischer 344 rats.

The effect of dietary benzylselenocyanate (BSC), a novel organoselenium compound and its sulfur analog, benzylthiocyanate (BTC), on hepatocarcinogenesis induced by azoxymethane (AOM) was investigated in male F344 rats. Eighty-one weanling rats were divided into 3 groups and were raised on a semipurified diet (control diet). Starting from 5 weeks of age, groups of animals consuming the control diet were fed one of the experimental diets containing 25 ppm BSC or BTC. An additional group was continued on the control diet. At 7 weeks of age, animals were given weekly sc injections of AOM (15 mg/kg body weight once weekly for 2 weeks). One week after the second AOM injection, those groups receiving BSC and BTC diets were transferred to the control diet and continued on this diet until termination of the experiment at 34 weeks after the last AOM injection. For quantitative analysis of enzyme-altered liver cell foci, glutathione S-transferase placental form was stained by an immunohistochemical technique. The results indicate that the incidence and the density of the enzyme-altered foci were significantly lower in AOM-treated rats fed the diet containing 25 ppm BSC (foci incidence 56%, foci density 2.43/cm2) than in AOM-treated animals fed the control diet (foci incidence 92%, foci density 4.79/cm2). The incidence of small altered foci was significantly inhibited in rats fed the BTC diet (35%) as compared to those fed the control diet (68%), but the degree of inhibition was more pronounced in animals fed the BSC diet than in those fed the BTC diet.

[Cosmetic cranioplasty using the bone chips and Biobond (EDH-adhesive): technical note].

A new and simple cosmetic procedure for the prevention of skin depression produced by burr-holes was presented. A mixture of the bone chips obtained at craniotomy and Biobond in a volume ratio of 7:3 was used to fill the bone defect of the burr-holes in 65 cases. The postoperative appearance was excellent cosmetically. This mixture had good plasticity, and could be formed into any irregular shape desired, and there was no increase in the incidence of infectious complications.

Chemoprevention of colon carcinogenesis by dietary organoselenium, benzylselenocyanate, in F344 rats.

The effect of feeding benzylselenocyanate (BSC) and its sulfur analogue, benzylthiocyanate (BTC), 2 wk before, during, and until 1 wk after carcinogen administration (initiation phase) on intestinal carcinogenesis induced by azoxymethane (CAS:25843-45-2) was studied in male F344 rats. Weanling rats were raised on a semipurified diet (AIN-76A diet; control diet). Beginning at 5 wk of age, groups of animals consuming the control diet were fed one of the diets containing 25 ppm BSC or BTC. An additional group was continued on the control diet. At 7 wk of age, all animals in 3 groups, except the vehicle-treated controls, were administered s.c. injections of azoxymethane (15 mg/kg body weight, once weekly for 2 wk). Animals were continued on the control diet and BSC and BTC diets until 1 wk after carcinogen treatment, when those groups receiving BSC and BTC diets were fed the control diet until termination of the experiment. Tissue and blood plasma glutathione peroxidase activity was measured in vehicle-treated animals fed the control diet and BSC and BTC diets for 5 wk. The results indicate that body weights were comparable among the various dietary groups. BSC in the diet significantly inhibited the incidence (percentage of animals with tumors) and multiplicity (tumors/animal) of adenocarcinomas in the colon and multiplicity of adenocarcinomas in the small intestine compared to those fed the control diet. BTC in the diet had no effect on colon and small intestinal tumors. Selenium-dependent glutathione peroxidase activity was significantly increased in kidneys and colon and small intestinal mucosae of animals fed the BSC diet compared to animals fed the BTC and control diets.

Effects of sodium cyanate in mice bearing B16 melanoma.

Sodium cyanate injected IP at a dose level of 200 or 250 mg/kg caused a 90% or greater inhibition of the incorporation of [3H]thymidine into DNA of B16 melanoma transplanted SC in mice. Despite the inhibitory effect of sodium cyanate on precursor incorporation into DNA, no significant effect on host survival was observed when sodium cyanate was administered as a single agent in the diet, in drinking water, or by IP injection to mice that had received IP transplants of B16 melanoma. The action of melphalan and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in prolonging the survival time of melanoma-bearing mice was not enhanced by combined treatment with sodium cyanate. However, combined injections of sodium cyanate and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) increased the survival of tumor-bearing mice significantly more than injections of BCNU alone at a lower dose than the maximum tolerated one. These data and other studies suggest that B16 melanoma may be less responsive to the action of sodium cyanate than are murine leukemic cells or rat hepatomas.

Phase-I clinical trial of sodium cyanate in patients with advanced colorectal carcinoma.

Sodium cyanate, a drug that selectively suppresses amino acid incorporation for protein synthesis in tumor tissue, was given to patients with advanced colorectal carcinoma who had failed to conventional therapy, with the purpose of assessing a maximum tolerable oral dose. At 35 mg/kg p.o. daily, the drug had to be stopped in approximately half (4) of the patients because of gastrointestinal toxicity (nausea, vomiting) and neurologic toxicity (hallucinations, disorientation). However, in 5 other patients, at the same dose, the drug was well tolerated for up to 147 days and for a total cumulative dose of 308 g. In this group of patients, sodium cyanate was stopped because of evidence of tumor progression. No hematologic toxicity was observed. We observed no therapeutic effects. We therefore recommend a starting dose of 30 mg/kg p.o. if a phase-II study is considered.

The treatment of sickle cell disease. A historical and chronological literature review of the therapies applied since 1910.

The available literature is reviewed with reference to earlier and present therapies. When possible, methods used in clinical trials with different substances are briefly described, also giving their historical background. The substances studied or methods used are reported in chronological order. A total of 117 references have been made. Of these only 14 reported controlled double blind clinical trials (5 with urea, 3 with alkalines, 2 with phenothiazines, 2 with antisludging agents and one each with the defibrinating agent Arvin and cyanate). The controlled trials could not confirm the benefits claimed for the substances in the prevention or treatment of sickle cell crises. Treatment of the crises is still symptomatic and conventional.