Terapia fotodinâmica: aspectos farmacológicos, aplicações e avanços recentes no desenvolvimento de medicamentos

Photodynamic Therapy (PDT) is a clinical procedure, which utilize a photosensitive compound and light. This is a new modality of treatment for cancer, aged related macular degenerescence (AMD), psoriasis, arthritis, arterial restenosis, etc which exhibits efficiency, less traumatic effects, low recovery time and few co-lateral effects. The first officially approved drug for PDT by the Food and Drug Administration (EUA) is Photofrinâ, which is applied for cancer. A new generation drug for PDT, Visudyneâ was recently approved to treat AMD; its photoactive compound is BPDMA, a benzoporphyrin mono-acid derivative (chlorin-type molecule). A concise history, technical information and some drugs for PDT are reported.

Microemulsões: estrutura e aplicações como sistema de liberação de fármacos

Depending on formula composition, microemulsions may be used as a vehicle for drug administration. In this work the main applicable parameters used in the development of pharmaceutical microemulsions (ME) are analyzed. The conceptual description of the system, theoretical parameters related to formation of internal phases and some aspects of ME stability are described. The pseudo ternary phase diagram is used to characterize ME boundaries and to describe different structures in several regions of the diagram. Some applications of ME as drug delivery systems for different administration routes are also analyzed. ME offer advantages as drug delivery systems, because they favor drug absorption, being in most cases faster and more efficient than other methods in delivering the same amount of drug.

Degree of hermeticity of a multicompartment compliance aid: Implications for the quality of professional pharmaceutical services

A multicompartment compliance aid (MCA) is a blister-type repackaging system that aims to facilitate drug administration and thereby increase patient adherence. One of the characteristics of the MCA that should be taken into account is the moisture permeability, since this atmospheric condition is one of the most important factors that can modify the stability of medicines. In the current paper we report the moisture permeability tests performed on a MCA according to the US Pharmacopeia. This information on the suitability of the device will help pharmacists implement a high-quality professional service.

Validação em métodos cromatográficos para análises de pequenas moléculas em matrizes biológicas

Chromatographic methods are commonly used for analysis of small molecules in different biological matrices. An important step to be considered upon a bioanalytical method's development is the capacity to yield reliable and reproducible results. This review discusses validation procedures adopted by different governmental agencies, such as Food and Drug Administration (USA), European Union (EU) and Agência Nacional de Vigilância Sanitária (BR) for quantification of small molecules by bioanalytical chromatographic methods. The main parameters addressed in this review are: selectivity, linearity, precision, accuracy, quantification and detection limits, recovery, dilution integrity, stability and robustness. Also, the acceptance criterions are clearly specified.

Desenvolvimento, produção e caracterização de nanocristais de fármacos pouco solúveis

Poorly soluble drugs have low bioavailability, representing a major challenge for the pharmaceutical industry. Processing drugs into the nanosized range changes their physical properties, and these are being used in pharmaceutics to develop innovative formulations known as Nanocrystals. Use of nanocrystals to overcome the problem of low bioavailability, and their production using different techniques such as microfluidization or high pressure homogenization, was reviewed in this paper. Examples of drugs, cosmetics and nutraceutical ingredients were also discussed. These technologies are well established in the pharmaceutical industry and are approved by the Food and Drug Administration.

Utilização de medicamentos durante a gravidez na cidade de Natal, Rio Grande do Norte, Brasil

OBJETIVO: estudar o uso de medicamentos por gestantes atendidas durante o pré-natal em unidades básicas do Sistema Único de Saúde (SUS) na cidade de Natal, rio Grande do Norte, Brasil. MÉTODOS: foram entrevistadas 610 grávidas, entre o primeiro e o terceiro trimestre de gestação, que compareceram para consulta pré-natal em unidades de saúde localizadas nos quatro distritos sanitários de Natal, entre maio e julho de 2006. Os dados foram coletados com entrevistas estruturadas, baseando-se em perguntas uso-orientadas e medicamento-orientadas. Os fármacos foram classificados de acordo com o Anatomical Therapeutic Chemical Classification System (ATC) e segundo critérios de risco para a gestação da Food and Drug Administration (FDA). Utilizou-se teste do chi2 para análise dos dados. RESULTADOS: eram utilizados 1.505 medicamentos, obtendo-se uma média de 2,4 drogas por mulher. O uso de pelo menos um fármaco na gravidez foi relatado por 86,6% das gestantes. As classes mais utilizadas foram os antianêmicos (35,6% dos medicamentos), analgésicos (24,9%), drogas para distúrbios gastrintestinais (9,1%) e vitaminas (7%). De acordo com a classificação do FDA, dos medicamentos empregados 42,7% pertencem a categoria A de risco; 27,1% à categoria B, 29,3% à categoria C; 0,3 à categoria D e nenhum à categoria X. Foram usados, no primeiro trimestre da gestação, 43,6% dos fármacos. Observou-se maior uso de medicamentos quanto maior a escolaridade e a renda familiar da mulher. A automedicação ocorreu em 12,2% dos medicamentos; esse índice foi maior no primeiro trimestre de gravidez e em gestantes de baixa escolaridade e multigestas. CONCLUSÕES: as gestantes de Natal estão sendo expostas a uma variedade de medicamentos, cuja segurança na gravidez ainda é incerta, o que exige prescrição criteriosa para evitar possíveis danos ao feto.

Uso de medicamentos no primeiro trimestre de gravidez: avaliação da segurança dos medicamentos e uso de ácido fólico e sulfato ferroso

OBJETIVO:Identificar o perfil de uso de medicamentos no primeiro trimestre de gravidez com ênfase na avaliação da segurança e na adoção do ácido fólico e do sulfato ferroso por gestantes em uma Unidade Básica de Saúde da região Sul do Brasil.MÉTODOS:Trata-se de estudo transversal aninhado a uma coorte de gestantes. Os medicamentos foram classificados segundo a Anatomical Therapeutic Chemical (ATC), e a segurança avaliada segundo a Food and Drug Administration (FDA) e a Agência Nacional de Vigilância Sanitária (ANVISA). Foi investigado o uso/prescrição de sulfato ferroso e ácido fólico segundo o protocolo do Ministério da Saúde.RESULTADOS:Foram incluídas 212 gestantes. Dessas, 46,7% estavam em uso de medicamentos no momento do diagnóstico da gravidez e 97,6% utilizaram medicamentos no primeiro trimestre gestacional. O percentual mais elevado de automedicação ocorreu antes do início do pré-natal (64,9%). Observou-se maior exposição a medicamentos de risco D e X, segundo a classificação do FDA, antes do início do pré-natal (23,0%). Entre as gestantes, 32,5% não seguiam o protocolo de uso de ácido fólico e sulfato ferroso do Ministério da Saúde. No total, 67,9% das gestantes tiveram exposição inadequada aos medicamentos. Houve diferença entre as proporções de medicamentos utilizados segundo a ATC, e os principais grupos anatômicos identificados foram os dos medicamentos que atuam no sangue e órgãos hematopoiéticos e anti-infecciosos de uso sistêmico. Na época do diagnóstico da gravidez, observou-se expressivo uso de medicamentos que atuam no sistema geniturinário e hormônios sexuais (16,2%), como anticoncepcionais orais, o que provavelmente está relacionado ao percentual de gestações não planejadas (67,0%), nessa mesma ocasião 4 gestantes utilizaram ácido fólico e 3 utilizaram o sulfato ferroso.CONCLUSÃO:Os resultados demonstram uso expressivo de medicamentos durante a gravidez. Mesmo que haja menor exposição aos medicamentos no momento do diagnóstico da gravidez, observa-se maior consumo de medicamentos de risco e da prática de automedicação nesse período.

Expression and distribution of connexin 32 in rat liver with experimentally induced fibrosis

The connexin 32 (Cx32) is a protein that forms the channels that promote the gap junction intercellular communication (GJIC) in the liver, allowing the diffusion of small molecules through cytosol from cell-to-cell. Hepatic fibrosis is characterized by a disruption of normal tissue architeture by cellular lesions, and may alter the GJIC. This work aimed to study the expression and distribution of Cx32 in liver fibrosis induced by the oral administration of dimethylnitrosamine in female Wistar rats. The necropsy of the rats was carried out after five weeks of drug administration. They presented a hepatic fibrosis state. Sections from livers with fibrosis and from control livers were submitted to immunohistochemical, Real Time-PCR and Western-Blot analysis to Cx32. In fibrotic livers the Cxs were diffusely scattered in the cytoplasm, contrasting with the control livers, where the Cx32 formed junction plaques at the cell membrane. Also it was found a decrease in the gene expression of Cx32 without reduction in the protein quantity when compared with controls. These results suggest that there the mechanism of intercellular communication between hepatocytes was reduced by the fibrotic process, which may predispose to the occurrence of a neoplastic process, taken in account that connexins are considered tumor suppressing genes.

Metabolic profile and ruminal and abomasal pH in sheep subjected to intravenous ranitidine

Resumo: Brazilian sheep production has intensified, predisposing sheep to an increased incidence of digestive disorders, such as abomasal ulcers. Ranitidine is used to prevent and treat this disease; however, there is little information on the parenteral use of this drug in adult ruminants. Few data exist on the concomitant metabolic changes and the behavior of the digestive system associated with its use. For this study, five healthy male sheep with ruminal and abomasal cannulas were used. A 5x5 Latin square experiment with a 2x2+1 factorial arrangement of the treatments was performed. Sheep treated with drug doses of 1 or 2mg/kg ranitidine administered intravenously every 8 or 12 hours were compared with the control group, was treated intravenously with 1 mL of physiological solution per 25 kg every 12 hours. Higher total protein concentrations, hemoglobin levels, as well as increased aspartate aminotransferase activity and increased abomasal pH for up to 150 min following drug administration were observed in all animals that received the drug, regardless of dose and frequency. The animals treated every 12 hours showed a decrease in leukocyte number compared with the control group and with the animals treated every 8 hours. Increased serum creatinine concentrations were observed in the animals treated every 8 hours. Treatments of 1mg/kg every 8 hours and 2mg/kg every 12 hours increased the red blood cell count and decreased the serum pepsinogen. All protocols studied were safe for healthy sheep, but 1mg/kg ranitidine every 8 hours and 2mg/kg ranitidine every 12 hours were the most effective protocols for gastric protection.

A simple HPLC-fluorescence method for the measurement of R,S-sotalol in the plasma of patients with life-threatening cardiac arrhythmias

R,S-sotalol, a ß-blocker drug with class III antiarrhythmic properties, is prescribed to patients with ventricular, atrial and supraventricular arrhythmias. A simple and sensitive method based on HPLC-fluorescence is described for the quantification of R,S-sotalol racemate in 500 µl of plasma. R,S-sotalol and its internal standard (atenolol) were eluted after 5.9 and 8.5 min, respectively, from a 4-micron C18 reverse-phase column using a mobile phase consisting of 80 mM KH2PO4, pH 4.6, and acetonitrile (95:5, v/v) at a flow rate of 0.5 ml/min with detection at lex = 235 nm and lem = 310 nm, respectively. This method, validated on the basis of R,S-sotalol measurements in spiked blank plasma, presented 20 ng/ml sensitivity, 20-10,000 ng/ml linearity, and 2.9 and 4.8% intra- and interassay precision, respectively. Plasma sotalol concentrations were determined by applying this method to investigate five high-risk patients with atrial fibrillation admitted to the Emergency Service of the Medical School Hospital, who received sotalol, 160 mg po, as loading dose. Blood samples were collected from a peripheral vein at zero, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0 and 24.0 h after drug administration. A two-compartment open model was applied. Data obtained, expressed as mean, were: CMAX = 1230 ng/ml, TMAX = 1.8 h, AUCT = 10645 ng h-1 ml-1, Kab = 1.23 h-1, a = 0.95 h-1, ß = 0.09 h-1, t(1/2)ß = 7.8 h, ClT/F = 3.94 ml min-1 kg-1, and Vd/F = 2.53 l/kg. A good systemic availability and a fast absorption were obtained. Drug distribution was reduced to the same extent in terms of total body clearance when patients and healthy volunteers were compared, and consequently elimination half-life remained unchanged. Thus, the method described in the present study is useful for therapeutic drug monitoring purposes, pharmacokinetic investigation and pharmacokinetic-pharmacodynamic sotalol studies in patients with tachyarrhythmias.

Hypomagnesemia in critically ill cancer patients: a prospective study of predictive factors

Hypomagnesemia is the most common electrolyte disturbance seen upon admission to the intensive care unit (ICU). Reliable predictors of its occurrence are not described. The objective of this prospective study was to determine factors predictive of hypomagnesemia upon admission to the ICU. In a single tertiary cancer center, 226 patients with different diagnoses upon entering were studied. Hypomagnesemia was defined by serum levels <1.5 mg/dl. Demographic data, type of cancer, cause of admission, previous history of arrhythmia, cardiovascular disease, renal failure, drug administration (particularly diuretics, antiarrhythmics, chemotherapy and platinum compounds), previous nutrition intake and presence of hypovolemia were recorded for each patient. Blood was collected for determination of serum magnesium, potassium, sodium, calcium, phosphorus, blood urea nitrogen and creatinine levels. Upon admission, 103 (45.6%) patients had hypomagnesemia and 123 (54.4%) had normomagnesemia. A normal dietary habit prior to ICU admission was associated with normal Mg levels (P = 0.007) and higher average levels of serum Mg (P = 0.002). Postoperative patients (N = 182) had lower levels of serum Mg (0.60 ± 0.14 mmol/l compared with 0.66 ± 0.17 mmol/l, P = 0.006). A stepwise multiple linear regression disclosed that only normal dietary habits (OR = 0.45; CI = 0.26-0.79) and the fact of being a postoperative patient (OR = 2.42; CI = 1.17-4.98) were significantly correlated with serum Mg levels (overall model probability = 0.001). These findings should be used to identify patients at risk for such disturbance, even in other critically ill populations.

Intravenous dipyrone for the acute treatment of episodic tension-type headache: A randomized, placebo-controlled, double-blind study

Acute headaches are responsible for a significant percentage of the case load at primary care units and emergency rooms in Brazil. Dipyrone (metamizol) is easily available in these settings, being the most frequently used drug. We conducted a randomized, placebo-controlled, double-blind study to assess the effect of dipyrone in the acute treatment of episodic tension-type headache. Sixty patients were randomized to receive placebo (intravenous injection of 10 ml saline) or 1 g dipyrone in 10 ml saline. We used seven parameters of analgesic evaluation. The patients receiving dipyrone showed a statistically significant improvement (P<0.05) of pain compared to placebo up to 30 min after drug administration. The therapeutic gain was 30% in 30 min and 40% in 60 min. The number of patients needed to be treated for at least one to have benefit was 3.3 in 30 min and 2.2 in 60 min. There were statistically significant reductions in the recurrence (dipyrone = 25%, placebo = 50%) and use of rescue medication (dipyrone = 20%, placebo = 47.6%) for the dipyrone group. Intravenous dipyrone is an effective drug for the relief of pain in tension-type headache and its use is justified in the emergency room setting.

Effect of one-week ethanol treatment on monoamine levels and dopaminergic receptors in rat striatum

We studied the effects of ethanol on the levels of norepinephrine, dopamine, serotonin (5-HT) and their metabolites as well as on D1- and D2-like receptors in the rat striatum. Ethanol (2 or 4 g/kg, po) was administered daily by gavage to male Wistar rats and on the 7th day, 30 min or 48 h after drug administration, the striatum was dissected for biochemical assays. Monoamine and metabolite concentrations were measured by HPLC and D1- and D2-like receptor densities were determined by binding assays. Scatchard analyses showed decreases of 30 and 43%, respectively, in D1- and D2-like receptor densities and no change in dissociation constants (Kd) 48 h after the withdrawal of the dose of 4 g/kg. Ethanol, 2 g/kg, was effective only on the density of D2-like receptors but not on Kd of either receptor. Thirty minutes after the last ethanol injection (4 g/kg), decreases of D2 receptor density (45%) as well as of Kd values (34%) were detected. However, there was no significant effect on D1-like receptor density and a 46% decrease was observed in Kd. An increase in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), a decrease in norepinephrine, and no alteration in 5-HT levels were demonstrated after 48-h withdrawal of 4 g/kg ethanol. Similar effects were observed in dopamine and DOPAC levels 30 min after drug administration. No alteration in norepinephrine concentration and a decrease in 5-HT levels were seen 30 min after ethanol (4 g/kg) administration. Our findings indicate the involvement of the monoaminergic system in the responses to ethanol.

Antinociceptive effect of novel pyrazolines in mice

The antinociceptive effect of six novel synthetic pyrazolines (3-ethoxymethyl-5-ethoxycarbonyl-1H-pyrazole (Pz 1) and its corresponding 1-substituted methyl (Pz 2) and phenyl (Pz 3) analogues, and 3-(1-ethoxyethyl)-5-ethoxycarbonyl-1H-pyrazole (Pz 4) and its corresponding 1-substituted methyl (Pz 5) and phenyl (Pz 6) analogues) was evaluated by the tail immersion test in adult male albino mice. The animals (N = 11-12 in each group) received vehicle (5% Tween 80, 10 ml/kg, sc) or 1.5 mmol/kg of each of the pyrazolines (Pz 1-Pz 6), sc. Fifteen, thirty and sixty minutes after drug administration, the mice were subjected to the tail immersion test. Thirty minutes after drug administration Pz 2 and Pz 3 increased tail withdrawal latency (vehicle = 3.4 ± 0.2; Pz 2 = 5.2 ± 0.4; Pz 3 = 5.9 ± 0.4 s; mean ± SEM), whereas the other pyrazolines did not present antinociceptive activity. Dose-effect curves (0.15 to 1.5 mmol/kg) were constructed for the bioactive pyrazolines. Pz 2 (1.5 mmol/kg, sc) impaired motor coordination in the rotarod and increased immobility in the open-field test. Pz 3 did not alter rotarod performance and spontaneous locomotion, but increased immobility in the open field at the dose of 1.5 mmol/kg. The involvement of opioid mechanisms in the pyrazoline-induced antinociception was investigated by pretreating the animals with naloxone (2.75 µmol/kg, sc). Naloxone prevented Pz 3- but not Pz 2-induced antinociception. Moreover, naloxone pretreatment did not alter Pz 3-induced immobility. We conclude that Pz 3-induced antinociception involves opioid mechanisms but this is not the case for Pz 2.

Effects of chronic ethanol treatment on monoamine levels in rat hippocampus and striatum

We studied the effects of ethanol on concentrations of noradrenaline (NE), dopamine (DA) and serotonin (5-HT) and their metabolites in rat hippocampus and striatum. Ethanol (2 or 4 g/kg, po, from a 20% aqueous solution) was administered daily to male Wistar rats (4-13 per group) for 30 days and animals were sacrificed 30 min or 48 h after the last administration. Monoamines were measured by HPLC and considered significant at P < 0.05. A 47% increase in 5-HT levels was observed in the hippocampus with 4 g/kg ethanol in the 30-min protocol. Ethanol (2 and 4 g/kg) decreased DA (2114.5 ± 126.4 and 1785.1 ± 234.2 ng/g wet tissue, respectively) and 3,4-dihydroxyphenylacetic acid (DOPAC, 1477.6 ± 132.1 and 1218.8 ± 271.7 ng/g wet tissue, respectively) levels, while the higher dose also decreased NE (159.8 ± 13.5), 5-HT (228.0 ± 46.8) and 5-hydroxy-3-indoleacetic acid (5-HIAA, 304.4 ± 37.2 ng/g wet tissue), in the striatum after a 48-h withdrawal as compared to controls (DA: 3063.9 ± 321.3; DOPAC: 2379.6 ± 256.0; NE: 292.8 ± 50.2; 5-HT: 412.4 ± 36.2; 5-HIAA: 703.9 ± 61.4 ng/g wet tissue). In the 30-min protocol, ethanol (2 or 4 g/kg) decreased striatal NE (66 and 70%) and DA (50 and 36%) levels. On the other hand, increases were seen in 5-HIAA (146 and 153%) and 5-HT (59 and 86%) levels. Ethanol (2 g/kg, po) increased the homovanillic acid (HVA)/DA ratio (129%) in the striatum in the 30-min protocol, while at the higher dose it increased the HVA/DA ratio in the 48-h protocol (61%). These results indicate alterations in monoamines, mainly in the striatum, after chronic ethanol, which are influenced by dose and by the length of time after the last drug administration.