RESUMEN
BACKGROUND AND PURPOSE: The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAA R) with three α- (α1, α2 and α5) and two γ- (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site. EXPERIMENTAL APPROACH: We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. KEY RESULTS: We find the sensitivity of GABAA R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2- and α1-subunit containing receptors associated with γ2- or γ1-subunits. Functional expression of the γ1-subunit is supported by siRNA-based knock-down experiments in γ2F77I mice. CONCLUSIONS AND IMPLICATIONS: GABAA R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism.
Asunto(s)
Benzodiazepinas/farmacología , Histamina/metabolismo , Neuronas/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Animales , Sitios de Unión , Moduladores del GABA/farmacología , Técnicas de Silenciamiento del Gen , Hipnóticos y Sedantes/farmacología , Hipotálamo Posterior/efectos de los fármacos , Hipotálamo Posterior/metabolismo , Masculino , Ratones , Ratones Mutantes , Neuronas/metabolismo , Subunidades de Proteína , ARN Interferente Pequeño/administración & dosificación , Receptores de GABA-A/metabolismoRESUMEN
The bile steroids (BS) cholic acid and chenodeoxycholic acid are produced in hepatocytes and in the brain. Nothing is known about neuronal actions of BS. Deficiency in a 27-hydroxylase enzyme coincides with reduced production of chenodeoxycholic acid (CDCA) and a relative increase in cholic acid in an inherited lipid storage disease, cerebrotendinous xanthomatosis, characterized by neurological dysfunctions, which can be treated by dietary CDCA. We have examined the modulation of hypothalamic network activity by nine common BS. Cholate and CDCA significantly reduced the firing of hypothalamic neurons and synchronized network activity with CDCA being nearly 10 times more potent. The synthetic BS dehydrocholate synchronized the activity without affecting the firing rate. Gabazine, a GABA(A) receptor antagonist, occluded synchronization by BS. Whole-cell patch clamp recordings revealed a block of NMDA- and GABA(A)-receptors by BS. Potencies of nine common BS differed between NMDA and GABA(A) receptors, however in both cases they correlated with BS affinities for albumin but not with their lipophilicity, supporting a direct action at ligand gated ion channels. GABAergic synaptic currents displayed a faster decay under BS. Our data provide new insight into extrahepatic functions of BS revealing their neuroactive potential.
Asunto(s)
Ácido Quenodesoxicólico/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Hipotálamo/efectos de los fármacos , Neuronas/efectos de los fármacos , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Animales Recién Nacidos , Ácido Quenodesoxicólico/metabolismo , Antagonistas de Aminoácidos Excitadores/metabolismo , Antagonistas de Receptores de GABA-A/metabolismo , Hipotálamo/metabolismo , Ratones , Neuronas/metabolismo , Técnicas de Placa-Clamp , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
BACKGROUND AND OBJECTIVES: Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised clinical trial evaluated patient assessment of the efficacy and tolerability of oral prolonged-release (PR) oxycodone when co-administered with oral naloxone PR. METHODS: Two hundred and two patients with chronic cancer- or non-cancer-related pain undergoing stable oxycodone PR therapy (40, 60 or 80 mg/day) were randomised to one of four intervention groups: 10, 20 or 40 mg/day naloxone PR or placebo. Following a 4-week maintenance phase, patients were followed-up for 2 weeks in which time they received oxycodone PR only. At the end of the maintenance phase, patients and investigators were asked to assess treatment efficacy and tolerability, as well as preference for the titration or maintenance phase. RESULTS: Patient and investigator global assessment of efficacy and tolerability improved with increasing naloxone dose. Efficacy was ranked as 'good' or 'very good' by 50.0%, 67.4% and 72.5% of patients in the 10, 20 and 40 mg naloxone PR dose groups, respectively, compared with 43.5% of patients in the placebo group. Patient assessment of tolerability was similar between treatment groups and placebo, being ranked as 'good' or 'very good' by 83.3%, 79.1% and 82.5% of patients in the 10, 20 and 40 mg/day naloxone PR dose groups, respectively, compared with 71.7% of patients in the placebo group. The maintenance treatment phase was preferred by patients in the naloxone groups. A 2 : 1 dose ratio of oxycodone to naloxone was also assessed. Efficacy was ranked as 'good' or 'very good' by 70.4% of patients treated with the 2 : 1 dose ratio compared with 43.5% of patients receiving placebo. Tolerability of the 2 : 1 dose ratio was ranked as being 'good' or 'very good' by 81.5% of patients compared with 71.1% for the placebo group and patients preferred the maintenance phase. CONCLUSIONS: The co-administration of oral naloxone PR with oxycodone PR improves patient assessment of analgesic opioid therapy for severe chronic pain, in terms of both efficacy and tolerability.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Estreñimiento/prevención & control , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Oxicodona/uso terapéutico , Dolor/tratamiento farmacológico , Adolescente , Adulto , Anciano , Analgésicos Opioides/efectos adversos , Enfermedad Crónica , Estreñimiento/inducido químicamente , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxicodona/efectos adversos , Dolor/etiología , Dimensión del Dolor , Satisfacción del Paciente , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The Striatum is involved in the regulation of movements and motor skills. We have shown previously, that the osmolyte and neuromodulator taurine plays a role in striatal plasticity. We demonstrate now that hereditary taurine deficiency in taurine-transporter knock-out (TAUT KO) mice results in disinhibition of striatal network activity, which can be corrected by taurine supplementation. Modification of GABAA but not glycine receptors (taurine is a ligand for both receptor types) underlies this disinhibition. Whole-cell recordings from acutely isolated as well as cultured striatal neurons revealed a decreased agonist sensitivity of the GABAA receptor in TAUT KO neurons in the absence of changes in the maximal GABA-evoked current amplitude. The striatal GABA level in TAUT KO mice was unchanged. The amplitude enhancement of spontaneous IPSCs by zolpidem was stronger in TAUT KO than in wild-type (WT) animals. Tonic inhibition was absent in striatal neurons under control conditions but was detected after incubation with the GABA-transaminase inhibitor vigabatrin: bicuculline induced a larger shift of baseline current in WT as compared to TAUT KO neurons. Lack of taurine leads to reduced sensitivity of synaptic and extrasynaptic GABAA receptors and consequently to disinhibition. These findings help in understanding neuropathologies accompanied by the loss of endogenous taurine, for instance in hepatic encephalopathy.
Asunto(s)
Cuerpo Estriado/fisiología , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/fisiología , Inhibición Neural/fisiología , Receptores de GABA-A/fisiología , Animales , Bicuculina/farmacología , Células Cultivadas , Cuerpo Estriado/citología , Femenino , GABAérgicos/farmacología , Antagonistas del GABA/farmacología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Glicoproteínas de Membrana , Ratones , Ratones Noqueados , Taurina/farmacología , Vigabatrin/farmacologíaRESUMEN
UNLABELLED: Moist wound treatment is a well recognized method for the treatment of aseptic acute and chronic wounds. While the moist environment is beneficial to the woundhealing process, it also increases the risk of bacterial superinfection. We here report on the results of a clinical phase-III-study in which we tested the effect of a new PVP-iodine liposomal hydrogel (Repithel) on split-thickness skin grafts. This formulation optimizes moist wound treatment by improving the cell proliferation rate while preventing wound infection. AIM: The aim of this phase-III-study was to analyse the efficacy and tolerance of Repithel in patients receiving meshed skin grafts. METHODS: 167 patients with transplantation wounds were either treated with lipid gauze alone (control group) or with lipid gauze and Repithel. In both groups the extent of neoepithelization, the frequency and severity of graft losses and the time until complete wound closure was achieved were determined. Analysis of the re-epithelization was achieved by photoplanimetry. Impedance measurements gave additional information on the regeneration of the epidermal barrier. RESULTS: Wounds receiving Repithel showed a significantly faster neoepithelisation than wounds which were treated with lipid gauze alone. Treatment with Repithel significantly reduced both the number of graft losses and the size of area lost. The time until wounds were closed completely was significantly shorter in patients receiving Repithel than in controls. The positive effects of Repithel on wound healing were especially observed in smokers, patients with chronic wounds, burns or infected wounds. CONCLUSIONS: Repithel supports healing of meshgraft transplants and reduces the risk of graft loss. Patients who heal poorly benefit particularly from the Repithel treatment.
Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Coloides/administración & dosificación , Apósitos Oclusivos , Povidona Yodada/administración & dosificación , Trasplante de Piel , Cicatrización de Heridas , Vendajes , Cosméticos , Quimioterapia Combinada , Humanos , Vaselina , Trasplante de Piel/métodos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
BACKGROUND: Moist wound treatment improves healing at a possibly increased risk of bacterial infection and many local antiseptics impair healing. A moist treatment modality with efficient antimicrobial activity would be desirable. METHODS: In this monocentric, randomized, observer blinded, phase III study, a new hydrosome polyvinyl-pyrrolidone (PVP)-iodine preparation in hydrogel containing iodine in a 3% concentration (Repithel) was investigated for its effect on epithelialization in patients receiving meshed skin grafts. Grafts of 167 patients (donor site defects, burn wounds, or chronic defects) were dressed either with Repithel (n=83) covered with a gauze (Jelonet), or Jelonet-gauze only (n=84) until healing. RESULTS: Grafts receiving Repithel healed significantly earlier (9.4 days versus 12.4 days; p<0.0001) and faster than controls as measured by neo-epithelialization of mesh holes between days 7 and 11 (91.2+/-22.8% versus 82.3%+/-28.6, p<0.0001). A subgroup analysis showed that the effects on grafted burn wounds (p=0.0042) and chronic defects (p<0.0001) was more significant than on donor sites. Also a higher take rate of grafts (p=0.0053) and a reduced loss of grafts was observed with Repithel treatment (8 grafts versus 20 grafts) (p=0.0063, respectively). Smokers had improved graft take (p=0.0069) and higher rate of epithelialization (p=0.0040) compared to smokers of the control group. CONCLUSIONS: The results demonstrate significant clinical advantages of Repithel. This new local wound healing drug combines antisepsis and wound moisture efficiently resulting in significantly enhanced epithelialization, decreased transplant losses, and significantly improved healing especially in smokers.
Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Quemaduras/cirugía , Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Povidona Yodada/administración & dosificación , Trasplante de Piel/métodos , Cicatrización de Heridas/efectos de los fármacos , Epitelio , Femenino , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Mallas QuirúrgicasRESUMEN
BACKGROUND: Various standardized and/or validated models exist to test wound healing products. This article discusses their usefulness in clinical practice. OBJECTIVES: Major barriers to wound healing have been identified after intense interaction of research and practitioners. Although extensively tested, wound healing products are still associated with trial and error due to the high variability and complexity associated with the treatment of wounds. Therefore, the results of preclinical testing are compared and contrasted with clinical observations of a liposomal hydrogel containing 3% povidone-iodine (Repithel, PVP-ILH) to assess their expressiveness and to give the practitioner more guidance in application. METHODS: Testing of PVP-ILH included physicochemical testing according to ISO norms, testing in in vitro and in vivo models. The obtained results are compared to the clinical profile of the obtained product in randomized controlled trials and ultimately expressive case studies. RESULTS: PVP-ILH displays good local tolerance, the basis for use in sensitive and predamaged tissue. As observed in laboratory testing, it readily provides moisture and takes up limited amounts of moisture. This was also seen in the clinical testing, as the ability to keep wounds moist and incorporate a certain -- but not large -- amount of exudates. Clinical results also show clean, well-debrided wounds, an effect that (in the absence of an established model for wound cleansing) was traced to the hydrogel component carbomer. DISCUSSION: Recent consensus advocates the concept of wound bed preparation as a systematic approach to removing barriers to healing (TIME). Based on the results, tissue (removing non-viable tissue and debris) and moisture (balance) can now be better understood, and infection/inflammation (control) and edge (progressing, non-advancing or undermining wound edges) are reviewed together with previously published data to assess all aspects potentially impeding wound healing. CONCLUSION: PVP-ILH successfully removes barriers to wound healing, thus laying the foundation to high-quality wound closure. Results from many scientific disciplines can help the user to better understand a product, standardization of testing is the only way of making results comparable.
Asunto(s)
Antiinfecciosos Locales/farmacología , Fármacos Dermatológicos/farmacología , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacología , Povidona Yodada/farmacología , Cicatrización de Heridas/efectos de los fármacos , Absorción/efectos de los fármacos , Administración Tópica , Agar/farmacología , Animales , Antiinfecciosos Locales/administración & dosificación , Desbridamiento , Fármacos Dermatológicos/administración & dosificación , Gelatina/farmacología , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Técnicas In Vitro , Inflamación/prevención & control , Liposomas/administración & dosificación , Liposomas/farmacología , Povidona Yodada/administración & dosificación , Conejos , Pruebas Cutáneas , Agua/farmacología , Infección de Heridas/prevención & controlRESUMEN
To date, two new defects in the pentose phosphate pathway have been identified in patients with abnormalities in their polyol profiles. Some of them presented with neurological symptoms of so far unknown aetiology. The pathophysiological role of polyols, e.g. in the brain, is relatively unknown. We tested the neurotoxicity of polyols using a 'neurochip' model. After exposure of cortical rat neurons to D-arabitol and ribitol in increasing concentrations up to 10 mmol/L, the electrophysiological activity was measured. No acute effect on the spontaneous network activity of cortical neurons was observed. We speculate that polyols have only secondary effects on brain dysfunction.
Asunto(s)
Red Nerviosa , Neuronas/metabolismo , Ribitol/metabolismo , Alcoholes del Azúcar/metabolismo , Animales , Encéfalo/metabolismo , Metabolismo de los Hidratos de Carbono , Criopreservación , Relación Dosis-Respuesta a Droga , Electrofisiología , Humanos , Lidocaína/farmacología , Ratas , Tetrodotoxina/farmacologíaRESUMEN
The MAGhaler (Mundipharma GmbH) is a multidose dry powder inhaler (DPI) containing a novel formulation of drug and lactose compacted by an isostatic pressing technique (GGU GmbH). On actuation, a precise dose is metered from a compacted ring-shaped drug tablet. In this study, the lung deposition of salbutamol from this device has been assessed. Ten healthy non-smoking subjects completed a two-way cross-over study assessing the pulmonary deposition of salbutamol (200 microg) from the MAGhaler at high (60 l/min) and low (30 l/min) peak inhaled flow rates (PIFRs), representing maximal and sub-maximal inspiratory efforts. The formulation was radiolabelled with 99mTc, and lung and oropharyngeal depositions were quantified by gamma scintigraphyThe mean (SD)% ofthe delivered dose deposited in the lungs was 26.4 (4.3)% at 60 l/min and 21.1 (5.1)% at 30 l/min (P < 0.05), corresponding to mean lung depositions of 52.8 and 42.2 microg salbutamol, respectively. The distribution of drug within different lung regions did not vary significantly with inhaled flow rate. The data provided proof of concept for the novel inhaler device and the innovative drug formulation. In comparison with previous deposition data obtained with other DPIs, the lung deposition was relatively high, relatively reproducible (coefficient of variation 16% at 60 l/min) and relatively insensitive to the change in peak inhaled flow rate.
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Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Pulmón/efectos de los fármacos , Inhaladores de Dosis Medida , Adulto , Estudios Cruzados , Esquema de Medicación , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Cintigrafía , Estadísticas no Paramétricas , TecnecioRESUMEN
The microbicidal action spectrum of povidone-iodine (PVP-I) is broad - even after short onset times. Unlike local antibiotics and other antiseptic substances, no resistance develops. The high degree of bactericidal efficiency in respect of highly resistant gram-positive pathogenic micro-organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and enterococcus strains, is particularly significant for hospital hygiene. An in vitro study with 10 genotypically different MRSA isolates showed an optimum bactericidal effect (logarithmic reduction factor value >5) without protein load after just 30 s exposure and even in a dilution of Betaisodona solution (Mundipharma GmbH) of 1%. With protein load (0.2% albumin), the optimum in microbicidal effectiveness shifts to concentrations > or = 10% Betaisodona solution referring to an exposure time of 30 s. Since recent results are now also available on the toxicological safety of PVP-I preparations for the ciliated epithelium of the nasal mucosa and the good tolerability on skin and other mucous membranes is a known factor, a controlled clinical study is currently being carried out to eliminate colonizations of MRSA. Evidence has also recently been produced of the antiviral activity of PVP-I against herpes simplex, adeno- and enteroviruses, as well as its high degree of efficiency against Chlamydia. Hence alongside the classical fields of application, such as the disinfection of the skin and hands, mucosa antisepsis and wound treatment, there are also useful indications for the substance, i.e. rinsing of body cavities and joints and application to the eye.
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Antiinfecciosos Locales/uso terapéutico , Infección Hospitalaria/prevención & control , Enterococcus/efectos de los fármacos , Povidona Yodada/uso terapéutico , Staphylococcus aureus/efectos de los fármacos , Infecciones por Adenoviridae/tratamiento farmacológico , Infecciones por Chlamydia/tratamiento farmacológico , Oftalmopatías/tratamiento farmacológico , Herpes Simple/tratamiento farmacológico , Humanos , Resistencia a la MeticilinaRESUMEN
Moist treatment of wounds has been shown to improve epithelialization, however at an increased risk of bacterial infection. In this monocentric, randomized, open, phase II pilot study of polyvinyl pyrrolidone-iodine, a well-established topical antiseptic was tested in a new liposomal complexed form in patients receiving meshed skin grafts after burns or reconstructive procedures. Mesh skin graft sites of 36 patients were dressed either with the new polyvinyl-pyrrolidone-iodine liposome hydrogel formulation (Betasom hydrogel) (n = 21), or chlorhexidine-gauze (n = 15). After the first dressing change, wounds were assessed daily and documented every other day until they were healed. Methods of analysis included clinical assessment, photoplanimetry (rate of epithelialization), impedance measurement (moisture of surface and wound healing quality), patient's assessment of pain and other sensations, and thyroid hormones (T3, T4, and TSH). The rate of epithelialization was improved with Betasom hydrogel compared to chlorhexidine-gauze on day 11 (96.3% vs. 75.9% p = 0.056) and significantly on day 13 (100% vs. 82.3% p = 0.005), respectively. Impedance measurements showed an earlier return to normal values (day 9) in Betasom-hydrogel-treated wounds as opposed to chlorhexidine treatment (day 11). Clinical assessment indicated significantly better antiseptic efficacy (p = 0.002) and wound healing quality (p = 0.004) of Betasom hydrogel. Graft loss occurred at a significantly lower rate in Betasom treatment (n = 1; 5%), than in chlorhexidine treatment (n = 5; 35.7%) (p = 0.001). No relevant adverse events or clinically relevant changes of thyroid hormones were observed with Betasom hydrogel. The rationale of this new polyvinyl pyrrolidone-iodine liposomal formulation was based on the properties of liposomes that provide higher moisture to the wound surface, release PVP-iodine at a low rate, and target the substance more exactly by interaction with the cell surface. These initial clinical results show earlier epithelialization and better healing in wounds treated with polyvinyl pyrrolidone-iodine liposome hydrogel, which combines moisture and antisepsis, compared to wounds treated with a conventional antiseptic chlorhexidine-gauze.
Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Antiinfecciosos Locales/uso terapéutico , Povidona Yodada/administración & dosificación , Povidona Yodada/uso terapéutico , Trasplante de Piel , Cicatrización de Heridas/efectos de los fármacos , Infección de Heridas/prevención & control , Adulto , Epitelio/fisiología , Femenino , Humanos , Hidrogeles , Liposomas , Masculino , Proyectos PilotoRESUMEN
BACKGROUND: In topical wound treatment, the combination of anti-infectious therapy and a healing-promoting moisturization has not been accomplished yet. OBJECTIVE: Evaluation of a new topical drug consisting of a povidone-iodine (PVP-I) liposome hydrogel allowing for both antiseptic and moist treatment. METHODS: Pharmaceutical formulation of a complex of PVP-I (3%) and phosphatidylcholine in a hydrogel. In vitro, interaction of the complex with relevant micro-organisms was analysed by electron microscopy. Antimicrobial activity was investigated using Staphylococcus aureus in a suspension test. Tissue toxicity was examined by an explantation test in a rodent model. A randomized clinical study on efficacy and tolerability in wound healing was carried out on 35 patients with mesh grafts in parallel groups (PVP-I liposome hydrogel vs. Bactigras) for proof of concept in humans. RESULTS: A direct interaction of the PVP-I liposomes with micro-organisms by attachment to the cell surface was documented. A significantly better microbicidal activity and tissue tolerability of the PVP-I liposome hydrogel compared to conventional PVP-I formulations was shown. The results of the clinical study, especially measurements of neo-epithelization per time and transplant loss, demonstrate significant differences in favour of the PVP-I liposome hydrogel. CONCLUSION: The novel PVP-I liposome hydrogel combines microbicidal and wound healing activities resulting in enhanced epithelization.
Asunto(s)
Antiinfecciosos Locales/farmacología , Povidona Yodada/farmacología , Enfermedades Cutáneas Infecciosas/prevención & control , Cicatrización de Heridas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/ultraestructura , Química Farmacéutica , Escherichia coli/efectos de los fármacos , Escherichia coli/ultraestructura , Femenino , Humanos , Hidrogeles , Liposomas , Masculino , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica , Piel/efectos de los fármacos , Piel/patología , Enfermedades Cutáneas Infecciosas/microbiología , Trasplante de Piel , Staphylococcus aureus/efectos de los fármacosRESUMEN
Povidone-iodine (PVP-I) is a broad-spectrum microbicide with in vitro activity against bacteria, viruses, fungi and protozoans. A 5% solution of PVP-I proved to be highly effective in ophthalmic surgery for the prophylaxis of endophthalmitis. For the antiseptic treatment of eye infections a novel application form of PVP-I has been developed by using a PVP-I liposome complex which demonstrated an excellent antimicrobial efficacy. In this study it could be shown that the novel liposomal formulations containing 2.5 or 5% PVP-I were as active as the aqueous solution against herpes simplex virus type 1, adenovirus type 8, coxsackievirus A9 and Chlamydia trachomatis in cell culture referring to equal PVP-I concentrations. Long-term cytotoxicity experiments demonstrated a moderate cytotoxicity for both formulations with a better tolerability of the liposomal PVP-I formulation compared with the aqueous solution. There is no evidence for a genotoxic activity of these agents.
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Adenovirus Humanos/efectos de los fármacos , Antiinfecciosos Locales/farmacología , Chlamydia trachomatis/efectos de los fármacos , Enterovirus/efectos de los fármacos , Herpesvirus Humano 1/efectos de los fármacos , Soluciones Oftálmicas/farmacología , Povidona Yodada/farmacología , Animales , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Humanos , Liposomas , Masculino , Conejos , Células VeroRESUMEN
Oral mucositis is a frequent complication of radiochemotherapy. The origin of radiation-induced mucosal lesions is iatrogenic in nature, although further development of mucositis is essentially influenced by infection. It can be assumed that disinfection measures should decrease the severity of mucositis induced by radiochemotherapy. Therefore, in a prospective randomised study the efficacy of prophylactic oral rinsing with a disinfection agent was investigated. A randomised, prospective comparative trial was conducted with 40 patients undergoing radiochemotherapy of the head and neck region because of malignant disease. The treatment scheme consisted of irradiation to the tumour region and adjacent lymph nodes, with a total dose of 71.3 Gy, and simultaneous chemotherapy with carboplatin (60 mg/m2) on days 1-5 and 29-34. In all patients mucositis prophylaxis with nystatin, rutosides, panthenol and immunoglobulin was undertaken. In addition, 20 patients rinsed the oral cavity 4 times daily with povidone-iodine solution, while the group for comparison rinsed with sterile water. Clinical examination of the oral mucosa was performed weekly. Onset, grading and duration of mucositis were used as the main variables. Clinically manifest oral mucositis was observed in 14 patients in the iodine group (mean grading: 1.0) and in all 20 patients in the control group (mean grading: 3.0). The total duration (mean) of clinically observed mucositis was 2.75 weeks in treatment patients and 9.25 weeks in control patients. Median AUC (area under curve for grade vs duration) was 2.5 in the iodine rinsing patients and 15.75 in control patients. All differences found between the two groups were statistically significant. Increased iodine incorporation was not observed. A pathologic rise in thyroid hormone levels was not found in the iodine group. The results obtained indicate that incidence, severity and duration of radiochemotherapy-induced mucositis can be significantly reduced by oral rinsing with povidone-iodine in addition to the standard prophylaxis scheme. It can be concluded that rinsing with povidone-iodine is an easy, cheap and safe prophylactic method and can be recommended as a supportive treatment during antineoplastic treatment of the head and neck region.
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Antiinfecciosos Locales/administración & dosificación , Antineoplásicos/efectos adversos , Povidona Yodada/administración & dosificación , Radioterapia/efectos adversos , Estomatitis/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Terapia Combinada , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/patología , Mucosa Bucal/efectos de la radiación , Valores de Referencia , Estomatitis/tratamiento farmacológico , Estomatitis/etiología , Resultado del TratamientoRESUMEN
The microbicidal activity of the broad spectrum antimicrobial agent povidone-iodine is due to the strong oxidizing effects of free iodine on functional groups of amino acids, nucleotides and double bonds of unsaturated fatty acids. While the chemical mechanism of action of PVP-iodine is well understood, the actual sequence of events on the cellular and molecular level that causes rapid cell death has not been fully understood. The aim of this study was to elucidate effects of povidone-iodine on cell ultrastructure by electron microscopy and to monitor changes in enzyme activity and nucleotide efflux. Staphylococcus aureus, E. coli and C. albicans, medically relevant gram-positive, gram-negative and yeast micro-organisms, served as models. In the presence of povidone-iodine, rapid partitioning of the cytoplasm and pronounced coagulation of nuclear material was noted. Especially C. albicans exhibited a rapid, dose-dependent "loosening" of the cell wall; cells remained intact without lysis, rupture or wall breakage. Changes in beta-galactosidase and nucleotide concentrations were measured in E. coli. A rapid and dose-dependent loss of cellular beta-galactosidase activity was found, with no increase in the supernatant; loss of cellular nucleotides corresponded with an increase in the supernatant. Electron microscopy and biochemical observations support the conclusion that povidone-iodine interacts with cell walls of micro-organisms causing pore formation or generating solid-liquid interfaces at the lipid membrane level which lead to loss of cytosol material, in addition to enzyme denaturation. The chemical mechanism of action explains the fact that povidone-iodine does never generate resistance in micro-organisms.
Asunto(s)
Antiinfecciosos Locales/farmacología , Candida albicans/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Povidona Yodada/farmacología , Staphylococcus aureus/efectos de los fármacos , Candida albicans/metabolismo , Candida albicans/ultraestructura , Escherichia coli/metabolismo , Escherichia coli/ultraestructura , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica , Nucleótidos/metabolismo , Staphylococcus aureus/metabolismo , Staphylococcus aureus/ultraestructura , beta-Galactosidasa/metabolismoRESUMEN
Antiseptics that are locally applicable gain in significance due to their reliable microbicidal effectiveness and especially due to the rising incidence of highly resistant bacteria. This is because systemically applied antibiotics are not sufficient in eradicating superficial mucodermal bacteria and locally applied antibiotics can cause new resistance rapidly. The aim of this study was to demonstrate the microbicidal effectiveness of Poly(1-vinyl-2-pyrrodlidon)-iodine (PVP-iodine) against ten genotypical different methicillin resistant Staphylococcus aureus-(MRSA-) and five Enterococcus faecium-strains in a quantitative suspension test. The effectiveness of PVP-iodine with protein load (0.2% and 2% albumin) was tested against three MRSA strains. Without any protein load best microbicidial activity (KRt-value > 5) was obtained with concentrations in the range between 1-10% of the original Betaisodona solution after 30s exposure time. With protein load (0.2% albumin) the optimum in microbicidal effectiveness shifts to concentrations > or = 10% Betaisodona solution referring to an exposure time of 30s. With a protein load up to 2% albumin and an exposure time of 30s the bactericidal activity of the undiluted Betaisodona solution is already satisfying, while the 10% solution is not active till an exposure time of 5 min. Summing up PVP-iodine is recommended as a local mucodermal antiseptic against highly resistant gram positives.
Asunto(s)
Antiinfecciosos Locales/farmacología , Farmacorresistencia Microbiana , Enterococcus faecium/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Povidona Yodada/farmacología , Staphylococcus aureus/efectos de los fármacos , Enterococcus faecium/genética , Enterococcus faecium/crecimiento & desarrollo , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrolloRESUMEN
BACKGROUND: Oral mucositis is a frequent complication of radiochemotherapy. The origin of radiation-induced mucosa lesions is of iatrogenic nature although further development of mucositis is essentially influenced by infection. It can be assumed that disinfection measures should decrease the severity of mucositis induced by radiochemotherapy. Therefore, in a prospective randomised study the efficacy of prophylactic oral rinsing with a disinfection agent was investigated. PATIENTS AND METHOD: An open, randomised, prospective comparative trial was conducted with 40 patients undergoing radiochemotherapy of head and neck region due to malignant disease. The treatment scheme consisted of irradiation to tumor region and adjacent lymph nodes with a total dose of 71.3 Gy and simultaneous chemotherapy with carboplatin (60 mg/m2) on days 1 to 5 and 29 to 34. In all patients, a prophylaxis of mucositis with nystatine, rutosides, panthenol and immunoglobulin was undertaken. In addition, 20 patients rinsed oral cavity 4 times daily with povidone-iodine-solution, the comparative group rinsed with sterile water. Clinical examination of the oral mucosa was performed weekly. Onset, grading and duration of mucositis were used as main variables. RESULTS: Clinically manifested oral mucositis was observed in 14 patients of the iodine group (mean grading: 1.0) and all 20 patients of the control group (mean grading: 3.0). Total duration (mean) of clinically observed mucositis was 2.75 weeks in treatment patients and 9.25 in control patients. Median AUC (area under curve for grade vs duration) was 2.5 in iodine rinsing patients and 15.75 in control patients. All differences found between the 2 groups were statistically significant. Increased iodine incorporation was not observed. A pathological increase of thyroid hormone levels in the iodine group was not found. CONCLUSIONS: The gained results indicate that incidence, severity and duration of radiochemotherapy-induced mucositis can be significantly reduced by oral rinsing with povidone-iodine performed additionally to the standard prophylaxis scheme.
Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Antisépticos Bucales , Povidona Yodada/uso terapéutico , Radioterapia/efectos adversos , Estomatitis/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Antiinfecciosos Locales/administración & dosificación , Antifúngicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Terapia Combinada , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Inmunización Pasiva , Masculino , Persona de Mediana Edad , Nistatina/uso terapéutico , Pomadas , Ácido Pantoténico/análogos & derivados , Ácido Pantoténico/uso terapéutico , Povidona Yodada/administración & dosificación , Estudios Prospectivos , Dosificación Radioterapéutica , Rutina/análogos & derivados , Rutina/uso terapéutico , Estomatitis/inducido químicamente , Estomatitis/etiología , Factores de Tiempo , Vasodilatadores/uso terapéuticoRESUMEN
Dihydrocodeine is increasingly used in slow-release preparations for the treatment of chronic pain on step 2 of the "analgesic ladder" of the World Health Organization. Dihydrocodeine is suggested to act after O-demethylation to dihydromorphine. To test this possibility, experiments were carried out on rats under urethane anesthesia in which nociceptive activity was evoked by electrical stimulation of afferent C fibers in the sural nerve and recorded from neurons in the ventrobasal complex of the thalamus. Dihydrocodeine administered by intravenous injection reduced the evoked nociceptive activity in a dose-dependent manner. Like morphine, dihydrocodeine was capable of completely suppressing the evoked activity. Maximum depression was caused by 2 mg/kg, and the ED50 is 0.47 mg/kg. Naloxone (0.2 mg/kg) reversed the effect of dihydrocodeine (2 mg/kg). To inhibit O-demethylation of dihydrocodeine to dihydromorphine, metyrapone or cimetidine (50 mg/kg) was injected intraperitoneally 20 min before dihydrocodeine (1 and 2 mg/kg). This failed to markedly reduce the effect of dihydrocodeine. Dihydromorphine injected intravenously also reduced the evoked activity in a dose-dependent way. Maximum depression occurred at a dose of 4 mg/kg, and the ED50 is 0.97 mg/kg. Dihydrocodeine and dihydromorphine were equieffective when administered by intrathecal injection at a dose of 100 microg. It is concluded that dihydrocodeine causes analgesia independent of biotransformation to dihydromorphine.
Asunto(s)
Analgésicos Opioides/farmacología , Codeína/análogos & derivados , Tálamo/efectos de los fármacos , Analgésicos Opioides/metabolismo , Animales , Codeína/metabolismo , Codeína/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Dimensión del Dolor , Ratas , Ratas WistarRESUMEN
The natural element iodine has been used for more than 150 years to prevent infection and treat wounds. Yet only due to the development of iodophors has it become possible to use this highly efficient microbicide in a wide range of medical applications. The antimicrobial spectrum is universal. Its efficiency against clinically and epidemiologically significant new pathogens, such as methicillin-resistant Staphylococcus aureus and Enterococcus sp. has also been validated. No development of resistance has been determined. New data are also available on the excellent local tolerability of Betaisodona (povidone-iodine) preparations. On these grounds, a number of clinical fields exist in prophylaxis and therapy, for either once only or repeated applications: the disinfection of hands and skin, mucosa antisepsis, intra- and postoperative wound treatment, therapy of skin infections, burns and chronic wounds.
Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Antisepsia , Yodóforos/uso terapéutico , Povidona Yodada/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/prevención & control , Quemaduras/tratamiento farmacológico , Enfermedad Crónica , Enterococcus/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Mano/microbiología , Humanos , Cuidados Intraoperatorios , Resistencia a la Meticilina , Membrana Mucosa/microbiología , Cuidados Posoperatorios , Piel/lesiones , Piel/microbiología , Enfermedades Cutáneas Infecciosas/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/prevención & controlRESUMEN
The numbers of patients in intensive care units, with immunosuppression, and of elderly people increase in parallel with antibiotic-resistant microorganisms. Therefore the demand for an effective antisepsis increases. Moreover, it became evident that the pathophysiology and the outcome of infection are dependent on the properties of the microorganisms, e.g. synthesis of endo- and exotoxins, and on the host defense, the immune system. In addition to the microbicidal action, we studied the effects of povidone-iodine (PVP-I, Betaisodona) on the generation, release and activity of exotoxins (alpha-hemolysin, phospholipase C, lipase), as well as on granulocyte-derived tissue-destructive enzymes (elastase, beta-glucuronidase) and microbial-induced cytokine generation from human neutrophils. Our results clearly show that PVP-I does not only kill a wide range of bacteria but also inhibits the generation and release of bacterial exotoxins; furthermore, it also inactivates bacterial exotoxins as well as granulocyte-derived tissue-destructive enzymes and cytokines. These data support the usefulness and efficacy of PVP-I as an effective therapeutic agent to combat infection.