Endothelin receptor antagonists are an effective long term treatment option in pulmonary arterial hypertension associated with congenital heart disease with or without trisomy 21.

INTRODUCTION: Traditionally, treatment options for patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) are limited. Bosentan has been shown to improve pulmonary haemodynamics and exercise tolerance short term but long term clinical studies are lacking. AIM: To report long term efficacy and safety data with endothelin receptor antagonists (ERA) in patients with PAH associated CHD. METHODS: Prospective, open label, uncontrolled, single centre study of 53 patients (33 females, 17 Trisomy 21, mean age 34 ± 12 years) prescribed ERA (48 bosentan, 5 sitaxentan) from 2003 to August 2009. Outcome measurements of oxygen saturation (SaO2), WHO functional class, 6-minute walk test distance (6MWD) and adverse events were analysed. RESULTS: Mean duration of therapy was 15 ± 13 months in 53 patients with CHD. Four patients failed ERA, seven died (five progressive RHF) and one delisted from transplantation. No abnormal liver transaminases occurred on bosentan, with one case on sitaxentan. After 3, 6, 12, 18 and 24 months of treatment a significant improvement was seen in WHO functional class (mean 3.15 vs 2.8 vs 2.5 vs 2.5 vs 2.4 vs 2.4; p<0.01) and 6MWD (344 ± 18 vs 392 ± 17 vs 411 ± 17 vs 420 ± 17 vs 442 ± 18 vs 417 ± 23: p<0.0005, p<0.01) compared with baseline. The Trisomy 21 and PAH-CHD showed a significant improvement in 6MWD at 6 and 12 months (263 ± 24 vs 348 ± 29 vs 360 ± 32, p<0.01, p<0.05) respectively. No changes in SaO2, BNP, RV or LV function were demonstrated during follow-up. CONCLUSION: This large single centre study demonstrates that endothelin receptor antagonism is an effective and safe treatment in PAH associated CHD with or without Trisomy 21. The improvements in exercise tolerance are similar to reported benefits in other forms of PAH.

Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Type 2 diabetes is characterised by a progressive decline in HbA1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naïve patients with type 2 diabetes. PATIENTS AND METHODS: This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35-70 years, with HbA1c levels > 8.0% at diagnosis or > 7.0% at the 3-6-month follow-up. Patients were allocated to dietary management alone if the HbA1c level was 7.0-8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA1c was > 8.0%. Similar treatments were introduced at 3-6 months if the HbA1c was > 7.0%. Over a 3-year period, HbA1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA1c was < or = 7.0%. RESULTS: 416 patients were considered eligible for inclusion, with a mean (+/- SD) age of 54.1 +/- 9.2 years, BMI of 33.5 +/- 6.1 kg/m2, and baseline HbA1c of 8.6 +/- 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3-6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA1c values. Amongst those patients treated with the metformin/pioglitazone combination there was an estimated 0.1% increase in HbA1c/year. This was much less pronounced than the rises seen in HbA1c/year of 0.5% with the metformin/gliclazide and metformin/repaglinide combinations. CONCLUSIONS: This preliminary analysis of an observational, non-randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3-6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the beta-cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.

A structure-activity study of the neuropeptide PF1, SDPNFLRFamide, using the dorsal body wall muscle of the chicken nematode, Ascaridia galli.

The action of a range of N terminally modified peptides structurally related to the nematode peptide PF1, SDPNFLRFamide, has been investigated using a dorsal muscle strip preparation from the chicken nematode, Ascaridia galli. Acetylcholine contracts this muscle preparation in a concentration-dependent manner when applied in the range 1-100 microM with an EC50 value of 9 microM. These contractions are reduced in the presence of PF1 and its analogues, with a threshold effect of PF1 of around 1 nM and an IC50 value of 470 nM against 10 microM acetylcholine. All the PF1 analogues tested were less potent than PF1 in reducing the acetylcholine contractions, indicating the importance of the N terminal amino acids in the action of PF1 in this preparation.

Rifampicin and sodium fusidate reduces the frequency of methicillin-resistant Staphylococcus aureus (MRSA) isolation in adults with cystic fibrosis and chronic MRSA infection.

Nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA) to patients with cystic fibrosis (CF) frequently results in chronic respiratory tract carriage. This is an increasing problem, adds to the burden of glycopeptide antibiotic use in hospitals, and represents a relative contraindication to lung transplantation. The aim of this study was to determine whether it is possible to eradicate MRSA with prolonged oral combination antibiotics, and whether this treatment is associated with improved clinical status. Adult CF patients (six male, one female) with chronic MRSA infection were treated for six months with rifampicin and sodium fusidate. Outcome data were examined for six months before treatment, on treatment and after treatment. The patients had a mean age of 29.3 (standard deviation=6.3) years and FEV(1) of 36.1% (standard deviation=12.7) predicted. The mean duration of MRSA isolation was 31 months. MRSA isolates identified in these patients was of the same lineage as the known endemic strain at the hospital when assessed by pulsed-field gel electrophoresis. Five of the seven had no evidence of MRSA during and for at least six months after rifampicin and sodium fusidate. The proportion of sputum samples positive for MRSA was lower during the six months of treatment (0.13) and after treatment (0.19) compared with before treatment (0.85) (P<0.0001). There was a reduction in the number of days of intravenous antibiotics per six months with 20.3+/-17.6 on treatment compared with 50.7 before treatment and 33.0 after treatment (P=0.02). There was no change in lung function. Gastrointestinal side effects occurred in three, but led to therapy cessation in only one patient. Despite the use of antibiotics with anti-staphylococcal activity for treatment of respiratory exacerbation, MRSA infection persists. MRSA can be eradicated from the sputum of patients with CF and chronic MRSA carriage by using rifampicin and sodium fusidate for six months. This finding was associated with a significant reduction in the duration of intravenous antibiotic treatment during therapy.

Lr41, Lr39, and a leaf rust resistance gene from Aegilops cylindrica may be allelic and are located on wheat chromosome 2DS.

The leaf rust resistance gene Lr41 in wheat germplasm KS90WGRC10 and a resistance gene in wheat breeding line WX93D246-R-1 were transferred to Triticum aestivum from Aegilops tauschii and Ae. cylindrica, respectively. The leaf rust resistance gene in WX93D246-R-1 was located on wheat chromosome 2D by monosomic analysis. Molecular marker analysis of F(2) plants from non-critical crosses determined that this gene is 11.2 cM distal to marker Xgwm210 on the short arm of 2D. No susceptible plants were detected in a population of 300 F(2) plants from a cross between WX93D246-R-1 and TA 4186 ( Lr39), suggesting that the gene in WX93D246-R-1 is the same as, or closely linked to, Lr39. In addition, no susceptible plants were detected in a population of 180 F(2) plants from the cross between KS90WGRC10 and WX93D246-R-1. The resistance gene in KS90WGRC10, Lr41, was previously reported to be located on wheat chromosome 1D. In this study, no genetic association was found between Lr41 and 51 markers located on chromosome 1D. A population of 110 F(3 )lines from a cross between KS90WGRC10 and TAM 107 was evaluated with polymorphic SSR markers from chromosome 2D and marker Xgdm35 was found to be 1.9 cM proximal to Lr41. When evaluated with diverse isolates of Puccinia triticina, similar reactions were observed on WX93D246-R-1, KS90WGRC10, and TA 4186. The results of mapping, allelism, and race specificity test indicate that these germplasms likely have the same gene for resistance to leaf rust.

Regulation of the pharynx of Caenorhabditis elegans by 5-HT, octopamine, and FMRFamide-like neuropeptides.

More than fifty FMRFamide-like neuropeptides have been identified in nematodes. We addressed the role of a subset of these in the control of nematode feeding by electrophysiological recording of the activity of C. elegans pharynx. AF1 (KNEFIRFamide), AF2 (KHEYLRFamide), AF8 (KSAYMRFamide), and GAKFIRFamide (encoded by the C. elegans genes flp-8, flp-14, flp-6, and flp-5, respectively) increased pharyngeal action potential frequency, in a manner similar to 5-HT. In contrast, SDPNFLRFamide, SADPNFLRFamide, SAEPFGTMRFamide, KPSVRFamide, APEASPFIRFamide, and AQTVRFamide (encoded by the C. elegans genes flp-1; flp-1; flp-3; flp-9; flp-13, and flp-16, respectively) inhibited the pharynx in a manner similar to octopamine. Only three of the neuropeptides had potent effects at low nanomolar concentrations, consistent with a physiological role in pharyngeal regulation. Therefore, we assessed whether these three peptides mediated their actions either directly on the pharynx or indirectly via the neural circuit controlling its activity by comparing actions between wild-type and mutants with deficits in synaptic signaling. Our data support the conclusion that AF1 and SAEPFGTMRFamide regulate the activity of the pharynx indirectly, whereas APEASPFIRFamide exerts its action directly. These results are in agreement with the expression pattern for the genes encoding the neuropeptides (Kim and Li, 1999) as both flp-8 and flp-3 are expressed in extrapharyngeal neurons, whereas flp-13 is expressed in I5, a neuron with synaptic output to the pharyngeal muscle. These results provide the first, direct, functional information on the action of neuropeptides in C. elegans. Furthermore, we provide evidence for a putative inhibitory peptidergic synapse, which is likely to have a role in the control of feeding.

Hypoxia induces the expression of the pro-apoptotic gene BNIP3.

It has been shown that oxygen deprivation results in apoptotic cell death, and that hypoxia inducible factor 1 (HIF1) and the tumor suppressor p53 play key roles in this process. However, the molecular mechanism through which hypoxia and HIF1 induce apoptosis is not clear. Here we show that the expression of pro-apoptotic gene BNIP3 is dramatically induced by hypoxia in various cell types, including primary rat neonatal cardiomyocytes. Overexpression of HIF1alpha, but not p53, induces the expression of BNIP3. Overexpression of BNIP3 leads to a rather unusual type of apoptosis, as no cytochrome c leakage from mitochondria was detected and inhibitors of caspases were unable to prevent cell death. Taken together, these data suggest that HIF1-dependent induction of BNIP3 may play a significant role during hypoxia-induced cell death.

Characterization of glutamate-gated chloride channels in the pharynx of wild-type and mutant Caenorhabditis elegans delineates the role of the subunit GluCl-alpha2 in the function of the native receptor.

Glutamate-gated chloride (GluCl) channels are the site of action of the anthelmintic ivermectin. Previously, the Xenopus laevis oocyte expression system has been used to characterize GluCl channels cloned from Caenorhabditis elegans. However, information on the native, pharmacologically relevant receptors is lacking. Here, we have used a quantitative pharmacological approach and intracellular recording techniques of C. elegans pharynx to characterize them. The glutamate response was a rapidly desensitizing, reversible, chloride-dependent depolarization (EC(50) = 166 microM), only weakly antagonized by picrotoxin. The order of potency of agonists was ibotenate > L-glutamate > kainate = quisqualate. Ivermectin potently and irreversibly depolarized the muscle (EC(50) = 2.7 nM). No further depolarization was seen with coapplication of maximal glutamate during the maximal ivermectin response, indicating that ivermectin depolarizes the muscle by the same ionic mechanism as glutamate (i.e., chloride). The potency of ivermectin on the pharynx was greater than at any of the GluCl subunits expressed in X. laevis oocytes. This effect of ivermectin was abolished in the mutant avr-15, which lacks a functional GluCl-alpha2 subunit. However, a chloride-dependent, nondesensitizing response to glutamate persisted. Therefore, the GluCl-alpha2 subunit confers ivermectin sensitivity and a high-affinity desensitizing glutamate response on the native pharyngeal GluCl receptor.

Molecular, genetic and physiological characterisation of dystrobrevin-like (dyb-1) mutants of Caenorhabditis elegans.

Dystrobrevins are protein components of the dystrophin complex, whose disruption leads to Duchenne muscular dystrophy and related diseases. The Caenorhabditis elegans dystrobrevin gene (dyb-1) encodes a protein 38 % identical with its mammalian counterparts. The C. elegans dystrobrevin is expressed in muscles and neurons. We characterised C. elegans dyb-1 mutants and showed that: (1) their behavioural phenotype resembles that of dystrophin (dys-1) mutants; (2) the phenotype of dyb-1 dys-1 double mutants is not different from the single ones; (3) dyb-1 mutants are more sensitive than wild-type animals to reductions of acetylcholinesterase levels and have an increased response to acetylcholine; (4) dyb-1 mutations alone do not lead to muscle degeneration, but synergistically produce a progressive myopathy when combined with a mild MyoD/hlh-1 mutation. All together, these findings further substantiate the role of dystrobrevins in cholinergic transmission and as functional partners of dystrophin.

Physiological and pharmacological studies on nematodes.

Classical transmitters and neuroactive peptides act as transmitters or modulators within the central and peripheral nervous systems of nematodes, for example Ascaris suum and Caenorhabditis elegans. Acetylcholine (ACh) and gamma-aminobutyric acid (GABA) are respectively the excitatory and inhibitory transmitters onto somatic body wall muscle while 5-hydroxytrypamine (5-HT) is the excitatory transmitter onto pharyngeal muscle. 5-HT also reduces ACh-induced contractions of somatic muscle and this action of 5-HT is mediated through activation of adenylate cyclase while that on pharyngeal muscle is mediated through inositol phosphate activation. Glutamate, dopamine and octopamine also have transmitter roles in nematodes. Neuroactive peptides of the RFamide family can excite somatic muscle, for example, AF-1 (KNEFIRFamide), AF-2 (KHEYLRFamide), AF-3 (AVPGVLRFamide) and AF-4 (GDVPGVLRFamide) or inhibit and relax this muscle, for example, PF-1 (SDPNFLRFamide), PF-2 (SADPNFLRFamide) and PF-4 (KPNlRFamide). In addition PF-3 (AF-8) (KSAYMRFamide) has a biphasic action on pharyngeal muscle, excitation followed by inhibition while AF-1 only inhibits this muscle. The peptide effects can be either pre- or postsynaptic or both and are likely to be mediated through second messenger systems. In addition these peptides modulate the action of classical transmitters, particularly ACh.

Possible community immunity to small round structured virus gastroenteritis in a rural aboriginal community.

In April 1998 an outbreak of gastroenteritis affected visitors, but none of the Aboriginal residents, at a Territory Health Services luncheon in a rural Aboriginal community in Central Australia. The epidemiological features and identification of Small Round Structured Virus (SRSV) from two participants suggest that this was an outbreak caused by a SRSV. The attack rate in the visitors who ate or drank food at the luncheon was 73% (11 of 15). Seventeen Aboriginal residents were interviewed, none had gastroenteritis. The community potable water supply was contaminated with faecal bacteria around the time of the outbreak. No particular food could be implicated and laboratory examination of foods was not possible. It is proposed that past exposure to SRSVs may have resulted in the Aboriginal residents developing clinical immunity to infection. The process and consequences of the investigation in this community are also discussed.

Transforming growth factor-beta-mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation.

Upon transforming growth factor-beta (TGF-beta) treatment, Ramos cells, a B-cell lymphoma cell line, undergo apoptosis, as measured by annexin V labeling, DNA fragmentation, and propidium iodide staining. Apoptosis could be observed by 24 h after TGF-beta exposure and occurred before the development of a significant blockage of cell cycle progression. TGF-beta-mediated apoptosis was also accompanied by a strong induction of caspase-3 subfamily activity. Incubation of cells with the caspase inhibitor Z-VAD.FMK at 20 microM, but not at 10 microM, prevented TGF-beta-induced apoptosis from occurring. By comparison, caspase-3 subfamily activity was 87% inhibited at 10 microM Z-VAD.FMK and completely inhibited at 20 microM. Because of TGF-beta's well-established role of regulating gene transcription, the mRNA levels for proteins associated with apoptosis (Fas- and Fas-associated proteins, Bcl-2 family members, IAP proteins, and I kappa B) were also studied. After 24 h of TGF-beta treatment, the most significant mRNA changes occurred with Bcl-XL (two-fold decrease) and Bik (twofold increase). TGF-beta treatment also resulted after 48 h in a fivefold decrease in Bcl-XL protein levels, based on immunoblotting analysis. Therefore, TGF-beta-mediated apoptosis involves the activation of caspases. In addition, TGF-beta transcriptionally regulates Bcl-2 family members, Bcl-XL and Bik, to further influence the apoptosis process.

Cloning and characterization of human Jak-2 kinase: high mRNA expression in immune cells and muscle tissue.

We report on the cloning and sequence analysis of the mRNA coding for full-length human Janus kinase 2 (Jak2). The human form of Jak2 is 1132 amino acids in length with a M(r) of 131 KDa. It has 95% sequence similarity to pig and rat Jak2. The highest level of mRNA expression was found in the spleen, peripheral blood leukocytes, and testis. Also a significantly high level of Jak2 mRNA was found in heart and skeletal muscle. Northern blot analysis showed three mRNA species in all tissues tested, except heart and skeletal muscle, of 7.6, 5.9, and 4.8 Kb. In skeletal muscle and heart, three mRNA species of 7.6, 4.8, and 3.9 Kb were identified. The catalytic domain of the human Jak2 was expressed and its specificity for phosphorylating peptide substrates derived from the gp130, STAT, and Jak3 molecules was determined and compared to that for human Jak1 and Jak3.

hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity.

hUBC9, an E2 ubiquitin conjugating enzyme, was identified by yeast two-hybrid screening and coprecipitation studies to interact with MEKK1 and the type I TNF-alpha receptor, respectively. Because both of these proteins regulate NFkappaB activity, the role of hUBC9 in modulating NFkappaB activity was investigated. Overexpression of hUBC9 in HeLa cells stimulated the activity of NFkappaB as determined by NFkappaB reporter and IL-6 secretion assays. hUBC9 also synergized with MEKK1 to activate NFkappaB reporter activity. Thus, hUBC9 modulates NFkappaB activity which, at least in part, can be attributed to its interaction with MEKK1 and the type I TNF-alpha receptor.

Mutations in the Caenorhabditis elegans dystrophin-like gene dys-1 lead to hyperactivity and suggest a link with cholinergic transmission.

Mutations in the human dystrophin gene cause Duchenne muscular dystrophy, a common neuromuscular disease leading to a progressive necrosis of muscle cells. The etiology of this necrosis has not been clearly established, and the cellular function of the dystrophin protein is still unknown. We report here the identification of a dystrophin-like gene (named dys-1) in the nematode Caenorhabditis elegans. Loss-of-function mutations of the dys-1 gene make animals hyperactive and slightly hypercontracted. Surprisingly, the dys-1 mutants have apparently normal muscle cells. Based on reporter gene analysis and heterologous promoter expression, the site of action of the dys-1 gene seems to be in muscles. A chimeric transgene in which the C-terminal end of the protein has been replaced by the human dystrophin sequence is able to partly suppress the phenotype of the dys-1 mutants, showing that both proteins share some functional similarity. Finally, the dys-1 mutants are hypersensitive to acetylcholine and to the acetylcholinesterase inhibitor aldicarb, suggesting that dys-1 mutations affect cholinergic transmission. This study provides the first functional link between the dystrophin family of proteins and cholinergic transmission.

An examination of two emergency breathing aids for use during helicopter underwater escape.

BACKGROUND: There is a paucity of published work in which the performance of Emergency Underwater Breathing Aids (EUBA) has been examined in the wide range of scenarios in which helicopter underwater escape may be necessary. In the present investigation two EUBA were examined: the Air Pocket (AP) rebreather and the Short Term Air Supply System (STASS) mini SCUBA set. METHOD: Young, healthy male subjects undertook simple simulated helicopter underwater escapes in water at 15 degrees C and/or 5 degrees C. During the immersions the subjects attempted to remain submerged for 60 s while traversing back and forth along a ladder secured at a depth of 1.25 m. At each temperature the subjects used AP and STASS twice. The subjects were dressed in the Royal Navy winter sea helicopter aircrew equipment assembly and an aircrew helmet. RESULTS: Both AP and STASS significantly extended the underwater survival time of individuals when compared to their maximum breath-hold time (BHT). It is clear from the measurements made of gas concentrations in AP; the volume of air used from STASS; and subjective responses, that the 60-s submersions were achieved more easily with STASS than AP. CONCLUSION: It is concluded that in conditions similar to those of the present experiment STASS will give a longer underwater duration than AP, but this benefit must be offset against the possible risk of pulmonary barotrauma associated with the use of STASS, as well as increased training and maintenance costs. Irrespective of the EUBA which is provided, in-water training, preferably including exposure to cold water, will significantly improve the ability of an individual to use it.

The effect of blood alcohol on the initial responses to cold water immersion in humans.

Many drowning victims have alcohol in their blood, but it is not clear whether there is a causal relationship. This study examined the effect of moderate alcohol consumption on the initial responses to cold water immersion. Sixteen subjects wearing swimming costumes undertook two, 3-min head-out seated immersions in water at 15 degrees C. One hour before immersion, subjects drank either 3.7 ml.kg body water-1 of 40% v:v alcohol as vodka, or an equivalent volume of water (control) mixed with squash. On immersion, the average blood alcohol concentration was 23 mmol.l-1 (105 mg.100 ml-1) after alcohol consumption and zero in the control condition. Respiratory frequency in the first 20 s of immersion was found to be reduced (P < 0.05) by 10% (a total of 2-3 breaths) after alcohol consumption compared to the control immersion. Tidal volume, heart rate, rectal temperature and skin temperatures did not differ significantly between immersions. It is concluded that moderate alcohol consumption does not attenuate the initial "cold shock" responses to a practically significant extent and is thus unlikely to reduce the risk of drowning on immersion in cold water.

Neural involvement in 5-hydroxytryptamine-induced net electrogenic ion secretion in the rat intestine in-vivo.

5-Hydroxytryptamine (5-HT) induces active electrogenic anion secretion by both the small intestine and the colon, responses that can be detected from measurements of transmural electrical activity. This approach was adopted to examine the involvement of neural mechanisms in 5-HT-induced secretion in rat proximal jejunum, distal ileum and proximal colon in-vivo. Under control conditions, 5-HT caused maximum rises in transintestinal potential difference of 4.7 +/- 0.3, 3.8 +/- 0.4 and 7.6 +/- 0.3 mV, respectively, with corresponding ED50 values of 28 +/- 3, 38 +/- 4 and 41 +/- 4 nmol kg-1 (n = 12). In each region examined a neural component in the secretory response to 5-HT was identified. Hexamethonium (22 mumol kg-1) reduced the 5-HT response in each region: in the jejunum and colon, it also attenuated the responses to the 5-HT3 agonist, phenylbiguanide and to 5-methoxytryptamine (5-MeOT), an agonist at all 5-HT receptors except 5-HT3, indicating that in these regions the nicotinic pathway can be activated by more than one 5-HT receptor subtype. Atropine (0.27 and 2.7 mumol kg-1) was found to have regional effects on the intestinal responses to 5-HT receptor agonists. In the jejunum, evidence for a pro-secretory muscarinic pathway which could be activated by more than one 5-HT receptor subtype was found. In the ileum and colon no muscarinic pro-secretory pathway was identified, indeed in the colon, an anti-secretory pathway may be present. This muscarinic anti-secretory pathway was observed with phenylbiguanide and 5-MeOT, but not 5-HT. Substance P release does not appear to be involved in mediating the intestinal secretory response to 5-HT. 5-HT-induced intestinal anion secretion may involve a direct secretory action on the enterocyte which can be modified by neurally-mediated pro-secretory and anti-secretory pathways, the balance between these processes varying down the length of the gut.

A phase II study of tamoxifen combined with cisplatin-interleukin 2 and alpha-interferon in metastatic melanoma.

Tamoxifen (TAM) has been reported to enhance cisplatin (CDDP) cytotoxicity in experimental and clinical melanoma studies. Based on our previous experience with sequential cisplatin-interleukin-2 (IL2)-interferon (IFN), we performed a phase II study of TAM combined with our original CDDP-IL2-IFN regimen in 22 pretreated metastatic melanoma patients. With a 41% response rate (95% CI, 21-61) we confirmed the interesting antitumor activity of CDDP-IL2-IFN combination; however, TAM enhanced neither the response rate nor the duration of response, but appeared to induce significantly more myelotoxicity, as compared to our previous results with CDDP-IL2-IFN alone. Whereas mechanisms by which TAM may modulate CDDP cytotoxicity in melanoma tumors remain unknown, the exact place of TAM, if any, and its safety in chemotherapeutic or chemoimmunotherapeutic combinations require further investigations.