Tuberculosis - Present Medication and Therapeutic Prospects.

BACKGROUND: Tuberculosis (TB) has been present in the history of human civilization since time immemorial and has caused more deaths than any other infectious disease. It is still considered one of the ten most common epidemiologic causes of death in the world. As a transmissible disease, it is initiated by rod-shaped (bacillus) mycobacteria. The management of tuberculosis became possible owing to several discoveries beginning in 1882 with the isolation of the TB bacillus by Robert Koch. The diagnosis of TB was enabled by finding a staining method for TB bacteria identification (1883). It was soon realized that a large-scale policy for the treatment and prevention of tuberculosis was necessary, which resulted in the foundation of International Union against Tuberculosis and Lung Diseases (1902). An antituberculosis vaccine was developed in 1921 and has been in therapeutic use since then. TB treatment regimens have changed over the decades and the latest recommendations are known as Directly Observed Treatment Short-course (DOTS, WHO 1993). METHODS: A search of bibliographic databases was performed for peer-reviewed research literature. A focused review question and inclusion criteria were applied. Standard tools were used to assess the quality of retrieved papers. RESULTS: A total of 112 papers were included comprising original publications and reviews. The paper overviews anti-TB drugs according to their mechanism of action. The chemical structure, metabolism and unwanted effects of such drugs have been discussed. The most recent treatment regimens and new drugs, including those in clinical trials, are also presented. CONCLUSION: Despite a 22% decrease in the tuberculosis fatality rate observed between 2000 and 2015, the disease remains one of the ten prime causes of death worldwide. Increasing bacterial resistance and expensive, prolonged therapies are the main reasons for efforts to find effective drugs or antituberculosis regimens, especially to cure multidrug-resistant tuberculosis.

Hepatitis C - New drugs and treatment prospects.

Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.

New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their application.

Mechanism of solvolysis of N-[2-(4-o-fluorophenylpiperazin-1-yl)ethyl]-2,5-dimethyl-1-phenylpyrrole-3,4-dicarboximide (PDI).

The stability of N-[2-(4-o-fluorophenylpiperazin-1-yl)ethyl]-2,5-dimethyl-1-phenylpyrrole-3,4-dicarboximide (PDI; a derivative with an analgesic activity) was studied in order to investigate its degradation mechanism and identify its degradation products in aqueous-organic solutions. The stability of PDI and its two degradation products (A and B) was performed with an HPLC method: (LiChrospher C18 column (250 x 4 mm LD., dp = 5 microm), mobile phase: 3.5 g/L solution of sodium lauryl sulfate and 1.6 mL of phosphoric acid(V)-acetonitrile (40:60, v/v), UV detector: 240 nm, flow rate: 1 ml/min). The identification of products A and B was conducted using HPLC-ES-MS and 1H- and 13C-NMR methods.

The stability of N-[2-(4-o-fluorophenylpiperazin-1-yl)ethyl]-2,5-dimethyl-1 -phenylpyrrole-3,4-dicarboximide in aqueous-organic solutions.

The first-order reaction of solvolysis of N-[2-(4-o-fluorophenylpiperazin-1-yl)ethyl]-2,5-dimethyl-1-phenylpyrrole-3,4-dicarboximide (PDI) was investigated as a function of pH at 333, 328, 323, 318 and 308 K in the pH range 1.11 - 12.78. The decomposition of PDI was followed by the HPLC method (Nucleosil 10-C8 column (250 x 4 mm I.D., dp = 10 microm), mobile phase: 0.018 mol/L ammonia acetate - acetonitrile (40: 60 v/v), UV detector: 240 nm, flow rate: 1 mL/min. Specific acid-base catalysis involves solvolysis of the undissociated molecules of PDI catalyzed by hydroxide ions and spontaneous solvolysis of the undissociated and monoprotonated forms of PDI under the influence of solvents. The thermodynamic parameters of the reactions--activation energy (E(a)), enthalpy (DH(#)), entropy (DS(#))--were calculated.

Stability of the crystalline form of cefaclor monohydrate and its pharmaceutical preparations.

The influence of temperature and relative air humidity on the stability of cefaclor monohydrate in crystalline form and in its pharmaceutical preparations (oral suspension and slow release tablets) was investigated. The process of degradation was studied by using high-performance liquid chromatography with ultraviolet (UV) detection, as described in the monograph of cefaclor in European Pharmacopoeia. The degradation of cefaclor monohydrate in substance, in oral suspension and tablets at relative air humidity RH > 50% is a first-order autocatalytic reaction relative to substrate concentration, while at 0% RH the degradation of cefaclor in substance is a first-order reaction relative to substrate concentration. The kinetic and thermodynamic parameters of degradation were calculated.

The stability of cefprozil in oral suspension CEFZIL.

The stability of cefprozil in oral suspension CEFZIL was studied by means of the stress stability test. Degradation was evaluated by using an HPLC method with UV detection (280 nm), as described in the monograph of Cefprozil for Oral Suspension, in USP 25. At increased temperature and relative air humidity the degradation of cefprozil in CEFZIL occurs as reversible-consecutive and parallel reactions. The reversible reaction of isomerization is approx. 10 times faster than the parallel degradation reaction of individual isomers. The first-order rate constants of the parallel reactions Z-cefprozil --> product 1 and E-cefprozil --> product 2 were determined at RH = 76.4% at T = 333, 338, 343, 348 and 353 K, and at T = 333 K and RH = 50.9, 66.5, 76.4 and 90.0%. The thermodynamic parameters E(a), deltaH(double dagger) and deltaS(double dagger) of these reactions were calculated.

A comparison of the stability of ertapenem and meropenem in pharmaceutical preparations in solid state.

The following first-order rate constants of the degradation of ertapenem in INVANZ and meropenem in MERONEM were determined: (a) in dry air at 363, 373, 378, 383, 388, 393 K; (b) at increased relative air humidity (76.4% RH) at 313, 323, 333 and 343 K; (c) at increased relative air humidity (50.9, 60.5, 66.5, 76.4% RH-ertapenem and 50.9, 66.5, 76.4 and 90.0% RH-meropenem) at 333 K. The dependence ln k(i) = f(RH%) was described by the equations: ln k(i) = (6.63+/-1.22) x 10(-2) x (RH%)-13.36 +/- 1.68 (ertapenem) and ln k(i) = (4.22 +/- 2.98) x 10(-2) x (RH%)-12.14 +/- 2.16 (meropenem). The dependence lnk(i)=f(1/T) was described by equations: ln k(i) =19.4 +/- 2.6-(9230 +/- 800)(1/T) for ertapenem, at 76.4% RH; ln k(i) = 11.5 +/- 4.9-(9880 +/- 1800)(1/T) for ertapenem in dry air; ln k(i) = 14.8 +/- 11.9-(7785 +/- 3905)(1/T) for meropenem, at 76.4% RH; ln k(i) = 37.6 +/- 7.73-(18385 +/- 2930)(1/T) for meropenem in dry air. The thermodynamic parameters E(a), DeltaH( not equal) and DeltaS( not equal) of the degradation of ertapenem and meropenem were calculated. The difference between the influence of temperature on the stability of ertapenem and meropenem was not significant at 76.4% RH. In dry air (363-393 K) this influence was greater in the case of meropenem. The degradation of ertapenem was slower in this temperature range. Humidity was a significant factor affecting the degradation of these antibiotics and it influenced their stability is similar ways.

Stability of ertapenem in aqueous solutions.

The kinetics of degradation of ertapenem was studied in aqueous solutions at 303, 313, 323 and 333 K and pH 0.42-12.5. Degradation was studied using two methods: HPLC (LiChrospher RP-18 column, 5 microm, 250 mm x 4 mm; mobile phase: methanol-phosphate buffer 25 mmol l(-1), pH 6.5 (15:85, v/v); flow rate--1.2 ml/min; detection UV--298 nm) and UV (294 nm). Specific acid-base catalysis involves: (a) hydrolysis of ertapenem, catalysed by hydrogen ions; (b) hydrolysis of ertapenem dianions catalysed by hydroxide ions; (c) spontaneous hydrolysis of zwitter ions and dianions of ertapenem under the influence of water. The thermodynamic parameters of these reactions--energy, enthalpy and entropy of activation were calculated. It was observed that buffer catalysis occurred in acetate, phosphate and borate buffers.

The stability of the amorphous form of cefuroxime axetil in solid state.

The stability of the amorphous form of cefuroxime axetil was studied by means of the stress stability test. The degradation was evaluated using the HPLC method with UV detection (278 nm), as described in the monograph of Cefuroxime Axetil in European Pharmacopoeia. Liquid chromatography was performed with a H5 SAS Hypersil column (5 microm particle size, 250 mmx4 mm), the mobile phase consisted of a mixture of 38 volumes of methanol and 62 volumes of a 23 g l-1 solution of ammonium dihydrogen phosphate, a flow rate of 1.2 ml min-1, and the internal standard was a solution of acetanilide in a mixture (1:1) of acetonitrile and water at a concentration of 0.2 mg ml-1. At an increased temperature at RH=0%, the degradation of cefuroxime axetil (CFA) diastereoisomers is the reversible first-order reaction, while that occurring in humid air (RH>25%) is the reversible first-order autocatalytic reaction with Delta3-isomers and E-isomers of cefuroxime axetil and cefuroxime as the main products.

The stability of Cefuroxime axetil in tablets.

The stability of cefuroxime axetil in BIORACEF tablets was studied by means of long term (298 K/60% RH), intermediate (303 K/65% RH), accelerated (313 K/75% RH) and stress stability tests. Changes in the concentration of cefuroxime axetil diastereoisomers A and B and their total was determined using the RP-HPLC method, as described in a monograph of Cefuroxime axetil tablets in the British Pharmacopoeia 2003. After 2 years of storage under long term, 1 year under intermediate and 6 months under accelerated storage conditions, the preparation of BIORACEF meets the quality requirements as regards both. the active substance content and chromatographic purity. Under stress conditions the decomposition of cefuroxime axetil diastereoisomers follows the first-order reversible autocatalytic reaction with delta3-isomers of cefuroxime axetil as the main product. The kinetic parameters of the decomposition reaction were calculated and compared with analogical parameters obtained for ZINNAT tablets stored in the same conditions.

Stability of ceftriaxone disodium in Biotrakson and Tartriakson.

The influence of temperature and relative air humidity on the stability of ceftriaxone disodium (CTN) in Biotrakson and Tartriakson was investigated. At RH = 0%, the degradation of ceftriaxone was the first-order reaction, while at RH from 50.9% to 76.4% it was an autocatalytic first-order reaction relative to the substrate concentration. The influence of temperature on the stability of CTN was described by the following equations in the case of Biotrakson: RH =0% ln k = (-23488 +/- 7320) x 1/T+ 45.1; RH = 76.4% ln k = (-9492 +/- 1128) x 1/F + 16.1, and for Tartriakson: RH = 0% ln k = (-23491 +/- 7370) x 1/T + 42.4; RH = 76.4% ln k = (-10397 +/- 3034) x 1/T + 18.8. The influence of humidity on the stability of Biotrakson was described by the following equation: ln k = (0.0823 +/- 0.0272) x RH% -17.0 and for Tartriakson ln k = (0.0895 +/- 0.0246) x RH% -17.6.

Stability of ceftazidime pentahydrate in medicinal preparations Biotum and Ceftim.

The influence of temperature and relative air humidity on the stability of ceftazidime in two different pharmaceutical preparations was investigated. The degradation of the substance studied was determined: (a) in dry air at 373, 378, 383, 388 and 393 K; (b) at air humidity RH = 76.4% at 323, 333, 343, 353 and 358 K; (c) in the humidity range 25.0 - 76.4% at 358 K. The decomposition of ceftazidime in these conditions is a first-order reaction relative to substance concentration. The kinetic and thermodynamic parameters of the degradation of ceftazidime were calculated and compared for the two pharmaceuticals. The study was conducted using the HPLC method on LiChrosorb RP-18 columns (250 x 4 mm) with 9% acetonitrile in 0.1 mole/L ammonium acetate as mobile phase and detection at 254 nm.

Stability of aztreonam in AZACTAM.

The influence of temperature and relative humidity on the stability of aztreonam in AZACTAM was investigated. Changes of the concentration of aztreonam were followed using the HPLC method with UV detection. The first-order rate constants of the reversible reaction of isomerization Z-aztreonam right harpoon over left harpoonE-aztreonam and the parallel reaction Z-aztreonam-->products were determined at RH=76.4% and T=313, 323, 333, 343 and 353 K, and at T=343 K and RH=50.9%, 60.5%, 66.5% and 76.4%. The thermodynamic parameters-energy, enthalpy and entropy of these reactions were calculated.

Evaluation of stability of cefuroxime axetil in solid state.

The effect of temperature and relative atmospheric humidity on the stability of the crystalline form of cefuroxime axetil (CFA) in solid state was investigated. CFA is a mixture of diastereomers A and B. Changes in the concentration of the two diastereomers (A and B) of CFA were recorded by means of HPLC with UV detection. The degradation of diastereomers of CFA occurring at 0% relative humidity (RH) of the ambient air is a reversible first order reaction, while that occurring in humid air (RH>50%) is an autocatalytic first order reaction relative to substrate concentration. Although it has been found, that diastereomer B is the more stable isomer, humidity has a stronger effect on this very diastereomer.

Kinetics of cefamandole nafate degradation in solid phase.

The influence of temperature and relative humidity (RH) on the stability of cefamandole (CM) nafate sodium in the solid phase was investigated. Changes in the concentration of cefemandole nafate sodium were recorded using HPLC with UV detection. The method was validated for the following parameters: selectivity, linearity, precision, limit of detection and sensitivity. It showed good linearity (r=0.9996) in the range 0.4 x 10(-4)-5.6 x 10(-4) g ml(-1) using a LiChrospher RP-18 column and as mobile phase acetonitryle-triethylamine (10% v/v, adjusted to pH 2.5 with phosphoric acid (84%) and diluted with water) (35:65). The degradation of CM occurring at 0% RH of the ambient air and at air humidity RH>50% is a first-order reaction relative to substrate concentration. The first-order rate constants (k) were determined for CM degradation in dry air at 373, 383, 388 and 393 K, at air humidity RH=76.4% at 323, 333, 343 and 353 K, and at 353 K at air humidity RH>50%. The kinetic and thermodynamic parameters of the decomposition were calculated.

Kinetics of degradation of cefetamet pivaloyloxymethyl ester and its hydrochloride in solid phase.

The influence of temperature and relative humidity on the stability of cefetamet pivoxil (CFP) and its hydrochloride (CFP.HCl) in solid phase was investigated. The process of degradation was studied using HPLC with UV detection. The degradation of CFP and CFP.HCl occurring at air humidity RH>50% is an autocatalytic first-order reaction with respect to substrate concentration, while at 0% relative humidity of the ambient air it is a first-order reaction relative to substrate concentration for CFP.HCl, and a reversible first-order reaction for CFP. The rate constants (k) were determined in dry air at 373 K, 378 K, 383 K, 388 K and 393 K; at air humidity RH = 76.4% at 333 K, .343 K, 353 K, 363 K and 373 K; and at 363 K at air humidity RH>50%. The kinetic and thermodynamic parameters of the degradation were calculated.

Stability of cefepime dihydrochloride monohydrate in solid state.

The pseudo first-order rate constants and thermodynamic parameters for the decomposition of cefepime in solid state in absence of humidity and at a relative humidity of 76.4% were calculated. The effect of humidity on the stability of cefepime dihydrochloride monohydrate in the humidity range 25.0%-76.4% at 358 K is described by the equation ln ki = (0.031 +/- 0.0043) x RH% - 10.08 +/- 0.22.