The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932–2015)

Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Pu?ca? used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the β-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Pu?ca? for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend.     

Effect of Bacopa monniera and Azadirachta indica on gastric ulceration and healing in experimental NIDDM rats

Gastric ulcers were induced in normal/NIDDM rats by various physical (2 hr cold restraint stress and 4 hr pylorus ligation) and chemical agents (ethanol, 1 ml/200 g, oral, 1 hr before; aspirin, 200 mg/kg, oral, 4 hr) and duodenal ulcers were induced by cysteamine (40 mg/200 g). Ulcer healing activity was studied in gastric ulcers induced by acetic acid (50%) and HCI (0.6 M). The result indicated that in both, normal and NIDDM rats, B. monniera extract (BME, 20-100 mg/kg) did not show any significant effect on blood glucose level, while A. indica (AIE, 250-1000 mg/kg) significantly decreased it. However, both BME (50 mg/kg) and AIE (500 mg/kg) showed significant anti-ulcer and ulcer-healing activities in normal and NIDDM rats. Further, the present results also indicated that the ulcer protective effects of BME was more pronounced in non-diabetic, while that of AIE was more in NIDDM rats. The anti-ulcer and ulcer-healing activities of BME and AIE may be due to their effects on various mucosal offensive and defensive factors, and correction of blood sugar level by AIE may help to have more ulcer protective effect in NIDDM rats.     

Effects of some oxidising agents,especially ammonium peroxysulfate,on sugar-beet pectins

Sugar-beet pectins contain feruloyl groups linked to the side chains of the rhamnogalacturonan backbone. Coupling reactions may cross-link these macro-molecules. Of several oxidising agents, only hydrogen peroxide-peroxidase and ammonium peroxysulfate were effective, indicating the involvement of free radicals. The effects of peroxysulfate and pectin concentrations, temperature, and the presence of some additives have been investigated mainly by viscometry and chromatography on Sepharose CL-2B. Depending on the concentration of the pectin, the reaction may be used to obtain either water-soluble products of increased molecular weight or gels.     

Side effects of chemotherapeutic oculo-toxic agents: a review

Patients with cancer are often prescribed chemotherapeutic substances that can be extremely oculo-visual-toxic in nature. Over the past several years, advances in cancer treatment have resulted in increased survival rates and patient longevity. Unfortunately, greater survival rates and longevity mean increased exposure to potentially harmful oculo-toxic substances and a higher incidence of oculo-visual side effects. Patients receiving chemotherapy may complain of symptoms that can imitate functional disorders such as blurred vision and photophobia (i.e. disorders of accommodation) and also include dry eyes or other symptomology commonly associated with disorders of the primary eye care system. These deleterious side effects affect the patient's quality of life and warrant our attention. It is essential that eye and vision care professionals appropriately diagnose and manage these induced disorders. This review presents the oculo-visual side effects of commonly used chemotherapeutic agents, the available treatment options when these unwanted side effects occur, and when known, the mechanism by which these agents cause oculo-visual toxicity.     

Schizophrenia: neural mechanisms for novel therapies

Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated "negative" symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-D-aspartate receptors, especially the cotransmitter D-serine, are promising. Stimulation of the alpha7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin.     

Effect of anthracyclines and mitoxantrone on oxygen uptake and ATP intracellular concentration in rat heart slices

The clinical use of anthracycline antibiotics is severely limited by dose-dependent cardiotoxicity. This accounts for our interest in differences on respiratory control of cardiac cells induced by two new anticancer agents epirubicin and mitoxantrone. Cellular oxygen uptake was measured for increasing drugs concentrations with a Warburg manometric apparatus and intracellular ATP by high-pressure liquid chromatography in rat heart slices incubated for 60′ with anthracyclines or mitoxantrone. Epirubicin inhibits endogenous respiration by 18% versus control while doxorubicin and mitoxantrone reduce oxygen uptake by 34 and 46%, respectively. ATP intracellular concentration was significantly reduced by all anticancer agents but particularly by mitoxantrone 86%.These results may be related to the biochemical side effects produced by these drugs on bioenergetics and cellular respiratory control.     

The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats

Aim of the study is to evaluate the anti-ulcer efficacy of the boswellic acids (BA), a triterpenoid known as anti-inflammatory/anti-arthritic agent, which is in clinical use. The reason for the study is that, the known non-steroidal anti-inflammatory drugs (NSAIDs) are full of side effects especially ulceration which is at the top. BA, although, used as an anti-arthritic agent yet it is not only devoid of ulcer production but protective also. The activity evaluation was done by the following universally accepted animal models viz., pyloric ligation, ethanol–HCl, acetylsalicylic acid, indomethacin and cold restrained stress-induced ulceration in rats. Results of the present study revealed that BA possess a dose dependent antiulcer effect against different experimental models. It showed different degree of inhibition of the ulcer score towards different ulcerogenic agents. The ulcer score against various ulcer inducing agents viz., pyloric ligation, ethanol/HCl, (acute and chronic) acetylsalicylic acid, indomethacin and cold restraint stress, was inhibited by 39%, 38%, 51%, 31%, 37% and 42% respectively at 250 mg/kg. From the data it is concluded that BA inhibited ulcer production non-specifically in all the experimental models, whereby, it is not possible to propose a single specific mechanism. Nevertheless it is possible that BA might be acting by increasing the gastric mucosal resistance and local synthesis of cytoprotective prostaglandins and inhibiting the leukotriene synthesis.     

Transglutaminase may mediate certain physiological effects of endogenous amines and of amine-containing therapeutical agents

Transglutaminase mediation of the effects of certain primary amines and alcohols may be important in receptor coupling to physiological responses. Many of the therapeutic and toxic side effects of drugs also may be related to their covalent linkage of glutamine residues of key regulatory proteins through the catalytic action of transglutaminase. This paper suggests that important therapeutic agents such as digoxin, tetracycline, adriamycin, and actinomycin D may have some effects related to transglutaminase action.     

Irsogladine, an anti-ulcer drug, suppresses superoxide production by inhibiting phosphodiesterase type 4 in human neutrophils

Neutrophil superoxide production is implicated in the pathogenesis of gastric mucosal damage induced by various ulcerative agents and Helicobacter pylori infection. We investigated here the effects of an anti-ulcer drug irsogladine [2, 4-diamino-6-(2, 5-dichlorophenyl)-s-triazine maleate] on cAMP formation in isolated human neutrophils. The cAMP level in human neutrophils was elevated by a phosphodiesterase (PDE) type 4 selective inhibitor rolipram, but not by any inhibitors of PDE1, PDE2 and PDE3. Irsogladine also increased cAMP formation in a concentration-dependent manner in neutrophils. A non-selective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) alone significantly increased cAMP level, whereas irsogladine was unable to further increase cAMP level in the presence of IBMX. Irsogladine inhibited concentration-dependently the superoxide (O(2)(-)) production induced by various stimuli including formyl-methionyl-leucyl-phenylalanine, opsonized zymosan, guanosine 5'-[gamma-thio] triphosphate, A23187 and phorbol 12-myristate 13-acetate. These effects of irsogladine were mimicked by rolipram, IBMX and dibutyryl cAMP. The inhibitory effects of irsogladine and rolipram on the O(2)(-) production were reversed by a protein kinase A inhibitor H-89. These results indicate that irsogladine inhibits the superoxide production in human neutrophils by the increase of cAMP content by PDE 4 inhibition, which in turn contributing to the anti-ulcer effects of irsogladine on gastric mucosal lesions associated with oxidative stress.     

β-Agonists as Antiobesity,Antidiabetic and Nutrient Partitioning Agents

In the past decade, the antiobesity, antidiabetic and nutrient partitioning activities of β-agonists have been extensively studied. The data generated from these compounds in experimental and farm animals have convincingly proved that body fat content and body weight can be modified to some degree by a metabolic agent without decreasing food consumption. Marginal antiobesity and antidiabetic activities in humans have been demonstrated with a few mixed β-agonists under certain conditions, but their utility is limited by side effects. The concept of a β₃-receptor rose from the study of these compounds and has been verified by the cloning and expression of this receptor from several species. Rat β₃-selective agonists have so far shown no antiobesity efficacy in humans. The resolution of several issues is critical for the discovery and development of efficacious antiobesity and antidiabetic agents with minimum side effects. Ultimately, the further investigation of these β-agonists and β-receptors should lead to a better understanding of the relationship between energy metabolism and feeding behavior.     

Aminocyclohexylsulfonamides: discovery of metabolically stable alpha(1a/1d)-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS)

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated by alpha(1) adrenergic receptor antagonists, but these drugs also produce side effects that are related to their subtype non-selective nature. To overcome this limitation, it was hypothesized that an alpha(1a/1d) subtype-selective antagonist would be efficacious while keeping side effects to a minimum. To discover alpha(1a/1d)-selective antagonists and improve metabolic stability of our previously reported compounds, we have designed and synthesized a series of (phenylpiperazinyl)- or (phenylpiperidinyl)-cyclohexylsulfonamides. By incorporating the information obtained from metabolism studies, we were able to discover several compounds that are both alpha(1a/1d) adrenoceptor subtype selective and show increased stability toward human liver microsomal metabolism. The selectivity profile of these compounds provides great improvement over the commercial drug tamsulosin, hence may pave the way to the development of new and efficacious therapeutic agents with reduced side effects.     

Statin-induced myositis: a commonly encountered or rare side effect?

PURPOSE OF REVIEW: Statins are well established as first-line agents for cholesterol lowering in cardiovascular disease, with accumulating evidence supporting their initiation and guidelines recommending treatment to lower LDL levels. Although generally well tolerated with few side effects, including headaches and gastrointestinal symptoms, concerns are raised regarding myopathy, which may lead to fatal rhabdomyolysis. This review examines current evidence on statin interactions, mechanism of injury and toxicity. RECENT FINDINGS: Significant myopathy is rare with an incidence of less than 0.5% of patients. Statin side effects may be dose-related, associated with other drug interactions that interfere with statin metabolic pathways through cytochrome p450 pathways or glucuronidation, or related to co-morbidities. Several theories have suggested that statin myotoxicity may be due to intracellular cholesterol depletion, or interference with oxidative phosphorylation pathways. Exact mechanisms are yet to be fully defined. Individuals with mixed dyslipidaemia may require combination therapy to achieve target lipid levels. No large-scale randomized trials have yet reported on the safety of combination therapy, although more recent studies may shed some light when they report. CONCLUSION: As most individuals on statins are 'high-risk' patients, they tend to be on multiple agents for cardiovascular disease which may interact with their statin. Progression of myalgia or myositis to rhabdomyolysis is rare (one in 30-100,000 patient-years of exposure), but if progressive muscle symptoms are ignored then fatalities can occur. When prescribing statins, physicians should be alert to potential risks and educate patients to report any potentially significant symptoms.     

Long-lasting cytoprotection after pentadecapeptide BPC 157, ranitidine, sucralfate or cholestyramine application in reflux oesophagitis in rats

Recently, the effectiveness of pentadecapeptide BPC 157 and other anti-ulcer agents, called 'direct cytoprotection', was evidenced in totally gastrectomized rats duodenum challenged with cysteamine 24 h after surgery, and sacrificed 24 h after ulcerogen application. The further focus was on the possibility that this effect could be seen over a more prolonged period (1, 2, 4 weeks), and in other parts of the gastrointestinal tract (i.e. oesophagus). After the removal of the stomach, the oesophagus and jejunum were joined by a termino-lateral anastomosis. The animals were euthanized 7, 14 or 28 d after surgery, when oesophagitis was blindly assessed both macroscopically (percentage of ulcerations areas) and microscopically (percentage of areas of ulcers, regeneration and hyperplasia; number of inflammatory cells - polymorphonuclear and mononuclear). Starting 24 h after surgery, the medication was continuously given in the drinking water, in a volume of 12.5 mL/rat daily, until euthanasia at the end of the observation period, i.e. 7, 14, 28 d following surgery. Based on previous experiments, the doses of agents were daily calculated per kg b.w. as follows: BPC 157 125 mg or 125 ng, cholestyramine 2.5 mg, ranitidine 125 mg, sucralfate 725 mg, whereas controls received 72.5 mL x kg(-1) water. In support of these initial findings, and considering gastrectomized acid-free rats as an ideal model for long-term cytoprotective studies as well, pentadecapeptide BPC 157 markedly attenuated termino-lateral oesophagojejunal anastomosis-reflux oesophagitis also over a quite prolonged period. This efficacy was only partly shared by other anti-ulcer agents. After 1-week-old oesophagitis (microscopical assessment), but not after 2 or 4 weeks, less damaged mucosa was noted in rats drinking ranitidine or sucralfate compared to controls. Similar effectiveness was noted for cholestyramine. The obtained results were supported also by inflammatory cell assessment. Compared with control values, BPC 157-treated groups consistently presented less polymorphonuclears and less mononuclears in all assessed periods. Interestingly, the values obtained in other treated groups showed no difference compared with control values. Thus, despite limitations, a generalization supporting a direct importance of a common cytoprotective approach, could be clearly provided. A useful, long-lasting cytoprotective activity (apparently more prominent in BPC 157 rats, than in reference agents, ranitidine, sucralfate, as well as cholestyramine) may be a likely suitable therapy in otherwise resistant reflux oesophagitis conditions.     

Quantitation by computerized visual image analysis of gastric mucosal lesions induced in mice and rats by non-steroidal anti-inflammatory drugs

A method is described for the quantative determination of gastric mucosal lesions induced by non-steroidal anti-inflammatory drugs in mice and rats. The area and number of gastric lesions present in formalin-fixed, glycerol-cleared mucosa is determined by computerized visual image analysis using instrumentation as described. The method is also applied to the determination of the protective effects of anti-ulcer agents (e.g. prostaglandin E2, pirenzepine). Thus this method affords unambiguous sensitive and determination of the percentage area of the mucosa damaged and the number of the lesions.     

Saw Palmetto Berry as a Treatment for BPH

Phytotherapeutic agents are often prescribed in Europe for the treatment of benign prostatic hyperplasia with lower urinary tract symptoms and are commonly used in the United States in over-the-counter preparations. Saw palmetto berry is the most popular of these agents, and in vitro some studies suggest that liposterolic extract of the plant has antiandrogenic effects that inhibit the type 1 and type 2 isoenzymes of 5alpha-reductase; however there are no clinical studies that show any decrease in serum dihydrotestosterone or prostate-specific antigen. Its efficacy in the treatment of lower urinary tract symptoms has not been conclusively proven. Clinical efficacy was suggested by a meta-analysis of Permixon, a formulation of saw palmetto, but the meta-analysis was done on suboptimal studies. One trial supports the equivalency of Permixon to finasteride in treating moderate to severe symptoms of benign prostatic hyperplasia, with less decrease in sexual function. However, without a control/placebo arm, the actual efficacy of the agents cannot be determined. Other than occasional gastrointestinal upset, no other side effects have been reported.     

Antibody conjugates and therapeutic strategies

Immunotherapeutics represent the largest group of molecules currently in development as new drug entities. These versatile molecules are being investigated for the treatment of a range of pathological conditions including cancer, infectious and inflammatory diseases. Antibodies can be used to exert biological effects themselves or as delivery agents of conjugated drug molecules. Site-specific delivery of therapeutic agents has been an ultimate goal of the pharmaceutical industry in order to maximize drug action and minimize side effects. Antibodies have the potential to realize this objective and in this review we will examine some of the main strategies currently being employed for the development of these diverse therapeutic molecules.     

The formation and enzymatic repair of DNA modifications caused by the haloethylnitrosoureas and related compounds.

The haloethylnitrosoureas are both useful antitumor agents and known carcinogens. These biological activities are believed to be associated with DNA modification, and some biologically significant lesions have been identified in DNA exposed to these agents. At the same time, DNA repair is a cause of resistance to treatment by these agents, and may also serve as protection against their carcinogenic effects.     

Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality

The hereditary forms of breast cancer identified by BRCA1 and BRCA2 genes have a defect in homologous DNA repair and demonstrate a dependence on alternate DNA repair processes by base excision repair, which requires poly(ADP-ribose) polymerase 1 (PARP-1). siRNA and deletion mutations demonstrate that interference with PARP-1 function results in enhanced cell death when the malignancy has a defect in homologous recombination. These findings resulted in a plethora of agents in clinical trials that interfere with DNA repair, and these agents offer the potential of being more selective in their effects than classic chemotherapeutic drugs. An electronic search of the National Library of Medicine for published articles written in English used the terms "PARP inhibitors" and "breast cancer" to find prospective, retrospective and review articles. Additional searches were done for articles dealing with mechanism of action. A total of 152 articles dealing with breast cancer and PARP inhibition were identified. PARP inhibition not only affects nonhomologous repair, but also has several other nongenomic functions. Mutational resistance to these agents was seen in preclinical studies. To date, PARP-1 inhibitors were shown to enhance cytotoxic effects of some chemotherapy agents. This new class of agents may offer more therapeutic specificity by exploiting a DNA repair defect seen in some human tumors with initial clinical trials demonstrating antitumor activity. Although PARP inhibitors may offer a therapeutic option for selected malignancies, the long-term effects of these agents have not yet been defined.     

Efforts to enhance the efficiency of tumor chemotherapy

Antiproliferative cytotoxic agents, of which several are still in clinical practice nowadays, could be characterized by low selectivity, narrow therapeutic index, medium or serious side effects and rapid formation of resistance. In the limited efficacy of these drugs several factors are playing a role such as the age, gender and pharmacogenetics of the patients, the morphological and biological feature of the tumor, moreover, pharmacokinetics and pharmacodynamics of the drugs. The question could be justified if there are methods which, by influencing the above parameters, are helpful in enhancing the efficacy and decreasing the toxic side effects of these drugs. Since a long time we have been interested in evaluating methods of preclinical and clinical level for increasing drug efficacy. The aim of this minireview is to give a short summary about our previous and present projects aiming: 1.) to characterize and mitigate toxic side effects of several cytotoxic agents; 2.) to decrease the toxic side effects and improve the antitumor effect of 5-fluorouracil by biochemical modulation and 3.) to study the possibility of individualized drug selection, based on the pharmacobiochemical and pharmacogenetic characteristics of the patients.