Optimal management of breakthrough cancer pain (BCP)

Breakthrough cancer pain (BCP) is common in patients with cancer, causing a negative impairment in quality of life. Recent diagnostic criteria allow for differentiation of background chronic pain and BCP, for which proportion of unpredictable episodes is very high. Five characteristics define BCP: rapid onset, high intensity, maximum intensity (minutes), mean duration 30 min, and unpredictable onset. Fentanyl is a synthetic opioid characterized by rapid absorption and start of the analgesic effects. In addition to comparing some of the marked differences between the four pharmaceutical forms of fentanyl marketed in Spain, this paper discusses the data collected in a comprehensive clinical trial program with fentanyl pectin nasal spray (FPNS), a formulation that takes advantage of the intranasal route and the PecSys™ technology. The FPNS formulation achieves analgesic action 5 min after application and significant pain relief at 10 min. FPNS, therefore, has key features to be an optimal treatment for BCP (AU)

Optimal management of breakthrough cancer pain (BCP).

Breakthrough cancer pain (BCP) is common in patients with cancer, causing a negative impairment in quality of life. Recent diagnostic criteria allow for differentiation of background chronic pain and BCP, for which proportion of unpredictable episodes is very high. Five characteristics define BCP: rapid onset, high intensity, maximum intensity (minutes), mean duration 30 min, and unpredictable onset. Fentanyl is a synthetic opioid characterized by rapid absorption and start of the analgesic effects. In addition to comparing some of the marked differences between the four pharmaceutical forms of fentanyl marketed in Spain, this paper discusses the data collected in a comprehensive clinical trial program with fentanyl pectin nasal spray (FPNS), a formulation that takes advantage of the intranasal route and the PecSys™ technology. The FPNS formulation achieves analgesic action 5 min after application and significant pain relief at 10 min. FPNS, therefore, has key features to be an optimal treatment for BCP.

Accurate estimation of dose distributions inside an eye irradiated with 106Ru plaques.

BACKGROUND: Irradiation of intraocular tumors requires dedicated techniques, such as brachytherapy with (106)Ru plaques. The currently available treatment planning system relies on the assumption that the eye is a homogeneous water sphere and on simplified radiation transport physics. However, accurate dose distributions and their assessment demand better models for both the eye and the physics. METHODS: The Monte Carlo code PENELOPE, conveniently adapted to simulate the beta decay of (106)Ru over (106)Rh into (106)Pd, was used to simulate radiation transport based on a computerized tomography scan of a patient's eye. A detailed geometrical description of two plaques (models CCA and CCB) from the manufacturer BEBIG was embedded in the computerized tomography scan. RESULTS: The simulations were firstly validated by comparison with experimental results in a water phantom. Dose maps were computed for three plaque locations on the eyeball. From these maps, isodose curves and cumulative dose-volume histograms in the eye and for the structures at risk were assessed. For example, it was observed that a 4-mm anterior displacement with respect to a posterior placement of a CCA plaque for treating a posterior tumor would reduce from 40 to 0% the volume of the optic disc receiving more than 80 Gy. Such a small difference in anatomical position leads to a change in the dose that is crucial for side effects, especially with respect to visual acuity. The radiation oncologist has to bring these large changes in absorbed dose in the structures at risk to the attention of the surgeon, especially when the plaque has to be positioned close to relevant tissues. CONCLUSION: The detailed geometry of an eye plaque in computerized and segmented tomography of a realistic patient phantom was simulated accurately. Dose-volume histograms for relevant anatomical structures of the eye and the orbit were obtained with unprecedented accuracy. This represents an important step toward an optimized brachytherapy treatment of ocular tumors.

Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight.

OBJECTIVE: This study was conducted to elucidate whether antagonistic targeting of the histamine H3 receptor increases hypothalamic histamine levels, in parallel with decreases in food intake and body weight. METHODS: The competitive antagonist potency of a recently synthesized histamine H3 receptor antagonist, NNC 38-1049, was studied in intact HEK293 cells expressing human or rat histamine H3 receptor, in which NNC 38-1049 was allowed to antagonize the effect of the H3 receptor agonist R-alpha-methylhistamine on isoprenaline-induced accumulation of cAMP. The affinity of NNC 38-1049 for a number of variants of the histamine receptor was also determined. Following single dosing of normal rats with NNC 38-1049, hypothalamic histamine levels were assessed by means of microdialysis. Plasma and brain levels of NNC 38-1049 and acute effects on food intake and energy expenditure were followed after oral doses of 3-60 mg/kg. Potential side effects were examined with rat models of behaviour satiety sequence (BSS), pica behaviour and conditioned taste aversion (CTA). Intakes of food and water together with body weight were recorded for 15 days during daily dosing of dietary obese rats. RESULTS: NNC 38-1049 was found to be a highly specific and competitive antagonist towards both human and rat histamine H3 receptors, and measurable amounts of NNC 38-1049 were found in the plasma of rats following single oral doses of 3-60 mg/kg and in the brain after 15-60 mg/kg. Following single intraperitoneal injections of NNC 38-1049 (20 mg/kg), significant increases in extracellular histamine concentrations were observed. The same dose did not change BSS or pica behaviour acutely, nor did it induce CTA following repeated administration for 7 days. Reductions in food intake were seen very soon after administration, and occurred in a dose-dependent fashion. Energy expenditure was unchanged, but the respiratory quotient (RQ) tended to decrease at higher doses, indicating an increase in lipid oxidation. Twice daily administration of 20 mg/kg of NNC 38-1049 in old and dietary obese rats resulted in sustained reduction of food intake throughout a 2-week study, and was associated with a highly significant (P<0.01) decrease in body weight compared with controls (-18.4+/-3.4 vs +0.4+/-2.7 g). The same dose of NNC 38-1049 produced an acute decrease of water intake, but 24 h intakes were not significantly changed. CONCLUSIONS: The results of this study strongly support the idea that an increase in the hypothalamic concentration of histamine produces a specific reduction of food intake and that this effect can be translated into a decrease in body weight.

Formación de Mediadores en Salud (VIH/SIDA) en un Centro Penitenciario / Training of HIV/AIDS health mediators in Prisons

En este artículo se describe un programa piloto de formación de mediadores en salud con relación alVIH cuyo objetivo primordial es la prevención de la infección por el VIH basado en la educación entre iguales como inspiradora del modelo. Al principio, seleccionamos un grupo multidisciplinar de profesionales a los cuales se les imparte un curso de formación. Posteriormente el grupo de profesionales traslada a los internos elegidos como mediadores en salud, la formación recibida en relación a la infección por el VIH y conductas de riesgo. La metodología básica engloba las tres áreas de aprendizaje, conocimientos, habilidades y actitudes. El trabajo en equipo resultaba fundamental, por ello, con los propios mediadores se programaron las diferentes actividades y acciones a realizar. Estas acciones incluirían actividades de gran grupo (charlas informativas, conferencias), actividades en las aulas con alumnos de la escuela, e incluso, propuestas punturales como la creación de "oficinas informativas" en los módulos. Los instrumentos de evaluación se alternaban en cada sesión. Las propias guías de cada taller, cuestionarios de conocimientos previos y posteriores al taller, escalas de satisfacción tanto para los internos como para los educadores así como impresiones recogidas por los evaluadores durante cada sesión eran las herramientas sobre las que se evaluaba constantemente el proceso de aprendizaje. El resultado obtenido confirma que los internos han adquirido conocimientos y habilidades suficientes para difundir mensajes de salud y prevención en relación a la infección por VIH. Después de haber puesto en marcha el programa hemos comprobado que la selección y motivación de los internos mediadores así como de los educadores implicados es, a la vez que el escollo más importante, el más necesario de salvar y superar; de él dependerá, en gran medida el éxito de todo el proyecto. Es necesario también incrementar los instrumentos evaluadores y de registro de las actividades que consideramos básicas para conocer el alcance real de las mismas en el colectivo-prisión, así como elementos de evaluación que garanticen información sustancial del cambio de hábitos y actitudes respecto a la infección por VIH (AU)

Sequential Nucleophilic Substitution: A Powerful Strategy for the Solid-Phase Production of Diverse Compound Libraries.

Polyfunctionalized, unprotected reagents (e.g. amines and thiols) can be used in the production of highly diverse compound libraries by performing sequential nucleophilic substitutions on support-bound polyelectrophiles (see scheme). The procedure reported here enables the efficient preparation of new beta-alanine derivatives which are suitable for lead discovery. E*=polyelectrophile, *=solid support.

[Generic drugs in psychopharmacology: pros and cons]. / Medicamentos genéricos en psicofarmacología: ventajas e inconvenientes.

Legislation to facilitate process for generic products has been enacted and generic drugs have entered the market soon after the patent for the brand-name agent have expired. In every instance, the rationale has been economic since it is generally assumed that the copies are not only therapeutically equivalent but also a great deal less expensive than the original. Sometimes this may be so. In this short review several comments are made in order to establish the variables that may influence bioequivalence between the brand-name drug and its generics. Among them emphasis is given to the particle sizes, pharmaceutical supply, choice of the right excipient, in order to avoid possible interactions with the drug, ingredient quality and purity, etc. All these variables must be carefully controlled. Even so a patient who is changed from a trade name product to a generic drug (or vice versa) may respond a little differently, which is important in Psychopharmacology. Two or more products should be considered biologically equivalent only when it can demonstrated that they fulfil three conditions: that they have the same pharmaceutical properties; that they are equally effective in therapeutic use and that they are tolerated equally by patients being treated for the indicated uses. Regulatory agencies could require subsequent versions of an original therapeutic product the type of data regarding pharmacology, toxicology and chemical assessment that was mandatory for the introduction of the original.

Monoclonal IgA antibodies protect against Acanthamoeba keratitis.

Acanthamoeba keratitis is a rare, yet sight-threatening corneal infection. Ocular infection does not appear to induce protective immunity as repeated corneal infections occur in both humans and experimental animals. However, we have recently demonstrated that activation of the common mucosal immune system by oral immunization with Acanthamoeba antigens protects both Chinese hamsters and pigs against ocular infection with A. castellanii. Protection correlates closely with the appearance of anti- Acanthamoeba antibodies in the tears. To test the hypothesis that oral immunization induces specific protective IgA antibodies, two monoclonal IgA antibodies specific for Acanthamoeba antigens were generated. Both antibodies detected epitopes on the surface of fixed Acanthamoeba trophozoites. When delivered intraperitoneally, one monoclonal antibody (14E4) was detected in stool and tear samples. This clone also protected naive animals against ocular challenge with Acanthamoeba trophozoites (43% infection rate compared to a 91% infection rate in animals receiving control IgA). In vitro functional studies showed that neither antibody induced encystment or directly killed Acanthamoeba trophozoites. However, both monoclonal anti- Acanthamoeba IgA antibodies produced a three-fold inhibition in the adherence of trophozoites to corneal epithelial cells in vitro. These data show that monoclonal anti- Acanthamoeba IgA antibodies can protect against Acanthamoeba keratitis and suggest that this occurs by inhibiting adhesion of the parasite to the corneal epithelium.

Vasoconstrictor and vasodilator effects of disopyramide on isolated rat vascular smooth muscle.

We investigated the effects of disopyramide on the isometric contractions and intracellular Ca2+ concentrations ([Ca2+]i) measured by Fura-2 fluorescence in isolated rat aorta and portal veins. Disopyramide at concentrations > or = 10(-5) M increased the duration and complexity of the spontaneous contractions in rat portal veins. At > 10(-6) M, it induced a concentration-dependent contraction in the rat aorta. This effect was endothelium independent, associated with an increase in [Ca2+]i and abolished in aortic rings incubated in Ca2+-free solution or pretreated with 10(-7) M nifedipine, suggesting that disopyramide increased [Ca2+]i through the activation of L-type Ca2+ channels. In aortic rings precontracted by KCl (30 and 80 mM), 80 mM KCl in a low-concentration (26.2 mM) Na+ solution or 10(-5) M noradrenaline, disopyramide induced a concentration-dependent relaxation. The relaxant response in 80 mM KCl-precontracted arteries was associated with a parallel reduction in [Ca2+]i, an effect attributable to its Ca2+ channel blocking properties. In contrast, disopyramide had no effect on the concentration-response curves to noradrenaline in the presence of nifedipine. Disopyramide also inhibited in a concentration-dependent manner the relaxation induced by levcromakalim in aortic rings precontracted by 30 mM KCl because of its inhibitory action on K(ATP) channels, whereas it had no effect on the relaxant response to sodium nitroprusside. These effects, together with the negative inotropic effects of the drug, may account for the increase in mean arterial pressure observed in disopyramide-treated patients and the profound hypotension observed after overdosages of disopyramide.

Impact of oral immunization with Acanthamoeba antigens on parasite adhesion and corneal infection.

PURPOSE: To determine whether oral immunization mitigates ongoing Acanthamoeba castellanii corneal infections in pigs. METHODS: Pigs were orally immunized with aqueous Acanthamoeba antigen mixed with cholera toxin (Ac-CT) or with saline, before or after ocular infection with A. castellanii. Mucosal secretions (i.e., tears and enteric wash) were tested for Acanthamoeba-specific IgA by enzyme-linked immunosorbent assay. Enteric washes were used as a source of IgA in assays measuring the binding of trophozoites to Chinese hamster corneal epithelial (CHCE) cells. RESULTS: Pigs immunized with Ac-CT before ocular challenge with A. castellanii had significant anti-Acanthamoeba IgA antibody titers in their tears and enteric washes and were protected against ocular infection. Enteric washes from orally immunized pigs inhibited trophozoite binding to CHCE cells in vitro by more than 75%. By contrast, pigs immunized after corneal infections had been established displayed keratitis of the same severity and duration as that in control pigs. However, 80% of the orally immunized animals were resistant to rechallenge with Acanthamoeba-laden contact lenses, whereas none of the control animals was resistant. CONCLUSIONS: Oral immunization with Ac-CT protects against Acanthamoeba keratitis when administered before corneal challenge. However, delaying oral immunization until after corneal disease is established fails to mitigate keratitis. The appearance of parasite-specific tear IgA correlates with protection and may act by preventing the parasite's binding to the corneal epithelium.

Effects of several class I antiarrhythmic drugs on isolated rat aortic vascular smooth muscle.

1. The vasorelaxant effects of seven NA+ channel blockers (i.e., class I antiarrhythmic agents), quinidine, disopyramide, imipramine, lidocaine, mexiletine, flecainide, and desipramine, were investigated in isolated endothelium-denuded rat aorta. 2. All drugs induced a concentration-dependent relaxation in aorta precontracted with either 80 mM KCl or 10(-5) M noradrenaline and, with the exception of mexiletine, they were more potent in inhibiting KCl-induced contractions. 3. The degree of inhibition of high KCl-induced contractions produced by quinidine and desipramine increased with the time of depolarization. Furthermore, the inhibitory effect of quinidine also increased in aorta preincubated in 40 mM KCl, whereas the inhibitory effects of other antiarrhythmics were almost similar in 5 or 40 mM KCl solution. 4. In conclusion, all these class I antiarrhythmic drugs inhibited Ca2+ entry through voltage- and receptor-gated channels as well as Ca2+ release from intracellular stores. As a consequence, they decrease the availability of intracellular free Ca2+ required for vascular smooth muscle contraction.

Stereoselective effects of the enantiomers, quinidine and quinine, on depolarization- and agonist-mediated responses in rat isolated aorta.

1. The effects of the two enantiomers, quinidine and quinine, were studied on depolarization- and agonist-induced isometric contractions in rat isolated thoracic aortic rings. 2. Quinidine or quinine (10(-6)M-3 x 10(-4)M) produced a concentration-dependent relaxation of 80 mM KCl-contracted rings, the pD2 values being 4.89 and 4.23, respectively. Thus, quinidine was about 4-5 times more potent than quinine. 3. The voltage-dependence of quinidine- and quinine-induced inhibition was studied in rings that had been incubated in 5 or 40 mM KCl Ca(2+)-free solution and then contracted by changing the bath solution to 100 mM KCl and 2 mM Ca2+. The inhibitory effects of quinidine were significantly enhanced when the rings were preincubated in 40 mM KCl (depolarizing conditions), when compared to normally polarized rings. In contrast, the effects of quinine were similar in 5 or 40 mM KCl solution. 4. The antagonism of noradrenaline (NA)-induced contractions by low concentrations of quinidine (< 10(-4)M) and quinine (< 3 x 10(-4)M) was competitive, as demonstrated by the concentration-dependent parallel rightward shift of the NA concentration-response curves (pA2 values 6.20 and 5.68, respectively, P < 0.05). 5. At low concentrations (< or = 3 x 10(-5)M), quinidine and quinine did not shift the concentration-response curve to 5-hydroxytryptamine (5-HT) or endothelin-1, whereas at higher concentrations they produced a downward shift of these curves. Quinidine and quinine (> 10(-4)M) inhibited to a similar extent both the phasic (induced in Ca(2+)-free media) and tonic responses (after restoring extracellular Ca2+) induced by 5-HT. 6. In conclusion, quinidine and quinine produced a stereoselective inhibition of depolarization and NA-induced contractions, quinidine being more potent than quinine. The inhibition of KCl-induced contractions could be attributed to inhibition of Ca2+ entry. Both drugs also behaved as competitive antagonists of alpha 1D-adrenoceptors. At high concentrations, quinidine and quinine also decreased the contractions induced by endothelin-1 and 5-HT in a non-stereoselective manner.

Voltage- and time-dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine.

1. Class I antiarrhythmic drugs (e.g. Na+ channel blockers) such as propafenone and quinidine also inhibit voltage-gated Ca2+ and K+ channels. In the present paper the voltage- and time-dependent inhibitory effects of propafenone and quinidine were studied on depolarization-induced vascular contractions and 45Ca2+ uptake in isolated endothelium denuded rat aorta and pig left descending coronary artery. 2. Quinidine and propafenone (10(-7) M -5 x 10(-5) M) produced a concentration-dependent relaxation of the contractions induced by 80 mM KCl. Propafenone was significantly more potent (P < 0.05) than quinidine in both rat aorta and pig coronary arteries but both drugs more potent (P < 0.05) in relaxing rat aorta than pig coronary arteries. In rat aortic rings, the relaxant effects of propafenone were unaffected by pretreatment with the Na+ channel blocker, tetrodotoxin. 3. The degree of inhibition produced after prolonged exposure (40 min) to propafenone and quinidine differed as the time of depolarization with 80 mM KCl was increased. Quinidine (3 x 10(-6) M, 10(-5) M and 3 x 10(-5) M) not only produced an inhibition at the very early stage of contraction, but also a time-dependent inhibition was observed. In contrast, propafenone (10(-6) M, 3 x 10(-6) M and 10(-5) M) produced a more marked concentration-dependent early block but only a mild time-dependent inhibition.4. The voltage-dependence of propafenone- and quinidine-induced inhibition, was studied in rat aorta and coronary arteries which had been incubated in 5 or 40mM KCl Ca2+-free solution and then contracted by changing the bath solution to 100 mM KCI and 2 mM CaCl2 solution. The inhibitor effects of quinidine were significantly enhanced (P <0.05) when the preparations were preincubated in 40 mMKCl (depolarizing) solution. In contrast, the effects of propafenone were quite similar in 5 or in 40 mMKCI solution.5. Quinidine, 10-5 M, produced a greater inhibition (P<0.05) of 100 mM KCl-stimulated 45Ca2+ uptake in aortic rings preincubated in depolarizing as compared to normal solution. In contrast, the inhibition produced by 3 x 10-6 M propafenone was similar in aortic rings incubated in 5 or 40 mM KCl solution.6.It is concluded that both quinidine and propafenone inhibited vascular smooth muscle contraction which could be attributed to reduced Ca2+ entry. The voltage- and time-dependent inhibitory effects of quinidine may reflect an increased binding of the drug to Ca2+ channels at depolarized potentials.

[Sensitivity and specificity of mouse peritoneal macrophages in the diagnosis of Chlamydia trachomatis infections]. / Sensibilidad y especificidad de los macrófagos peritoneales de ratón en el diagnóstico de infecciones por Chlamydia trachomatis.

We analyzed the sensitivity and specificity of mouse peritoneal macrophages (MPM) for the diagnosis of infection by Chlamydia trachomatis. Fifty seven samples were studied, 25 of them were from cervix and 32 were from bronchial aspiration, resulting 29 positive by immunofluorescence in McCoy cells and only 16 in MPM. The sensitivity and specificity for MPM were 55% and 96% respectively. We concluded that McCoy cells are the election cells for the diagnosis of Chlamydia infection. However, the MPM can be useful in the recuperation of this microorganism, if no other method is available.

Levels of insulin in the brains of rats modified by chronic administration of amphetamine, haloperidol and sulpiride.

Rats treated with two classic neuroleptic drugs at therapeutic doses, haloperidol (0.05 mg/kg/day i.p.) and sulpiride (3 mg/kg/day i.p.) showed a marked decline in cerebral levels of insulin (0.085 +/- 0.02 ng/g and 0.120 +/- 0.04 ng/g wet weight respectively) compared to the control group (0.383 +/- 0.05 ng/g wet weight), while rats given D-amphetamine bitartrate chronically (20 mg/kg/day p.o.) showed an increase in cerebral insulin (0.55 +/- 0.04 ng/g wet weight). Combining treatment with each neuroleptic drug and amphetamine, at the same doses, produced a significant decrease in cerebral levels of insulin (P less than 0.001) as in the amphetamine animals. In the groups of rats treated with haloperidol, sulpiride and both of these drugs combined with amphetamine, there was a slight increase in levels of serum insulin, more so in the neuroleptic groups. Serum glucose values did not vary.

Effect of beta-pyridyl-carbinol on platelet aggregation.

We studied the anti-platelet aggregation activity of beta-pyridyl-carbinol (b-PC) (Ronicol, Roche). This compound has a chemical structure similar to nicotinic acid and is therapeutically indicated in functional and organic circulatory processes. We determined the in vitro antiaggregation activity induced by ADP (4 microM) and collagen (20 micrograms/ml) using Cardinal and Flower's technique. Antithrombotic activity was assessed in rats by measuring the duration of ADP-induced (12.40 micrograms/kg i.v.) respiratory dysfunction in 2 groups: one given 17.14 mg/kg beta-pyridyl-carbinol for 8 consecutive days before testing and controls. In vitro and in vivo results were highly significant. Circulating platelet count increased in b-PC treated animals. Systolic and diastolic pressures remained unmodified during administration of b-PC.