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The paper reviews current treatments of acid-dependent diseases. The role of hydrochloric acid hypersecretion in pathogenesis of some gastroduodenal diseases is shown. Efficacy of antisecretory drugs from different groups is compared.
Some N-(pyrazol-5-yl)-2-nitrobenzamides, variably substituted in the pyrazole nucleus as well as in the amidic group, were reacted in acetic acid media with potassium nitrite and hydrochloric acid. The different chemical behaviour of the reacted pyrazole derivatives in relation to the substitution pattern in both the pyrazole nucleus and the amidic group, was observed. All compounds isolated from the reaction mixtures (4-nitroso, 4-nitro, 4-diazo and 4-chloro derivatives) were evaluated by the agar diffusion method for their "in vitro" growth inhibitory activity against Candida albicans (our collection), Candida tropicalis ATCC 13803, Saccharomyces cerevisiae ATCC 36375, Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The 1-methylpyrazole derivatives showed larger inhibition zones than the 1-phenyl ones in the antimicrobial tests.
With an ex vivo, isolated, ventilated, perfused canine pulmonary lobe, the effects of various levels of positive end-expiratory pressure (PEEP) were evaluated following acid injury. Following intrabronchial instillation of hydrochloric acid, eight lobes were ventilated with 5 cm of H2O of PEEP, 12 lobes with 10 cm of PEEP, and eight lobes with 15 cm of PEEP during a 4 hour perfusion period. Blood flow was kept constant in all preparations. Lobes with 5 cm of PEEP developed a 39% intrapulmonary shunt and increased their weight by 220%. When PEEP was increased to 10 cm, weight gain was similar (184%), but shunting decreased markedly, to 7%. When PEEP was increased further to 15 cm, shunting remained low (13%), but weight gain increased markedly, to 411% of the initial lobe weight. This study demonstrates the beneficial effects of PEEP in aspiration pneumonia, but it also points out that increasing levels of PEEP can magnify acid-pulmonary injury by causing a further increase in interstitial and intralveolar edema.
The experiments were performed on dogs with isolated pouches (according to Pavlov, Heidenhain and Gregory) to study the action of antidiuretic hormone (ADH) on gastric secretion produced by a food irritant (100 g of meat) and by administration of histamine and pentagastrin. ADH was shown to exert an inhibitory action on gastric secretion induced by food or humoral irritants in dogs with isolated pouches according to Pavlov and Heidenhain. In dogs with completely denervated isolated pouches, food irritant-induced gastric secretion was suppressed for 2 1/2--3 1/2 h. Then it exceeded the control level. During ADH administration the total acidity and the content of free hydrochloric acid noticeably decreased as compared to control. There was also a clear-cut tendency to a reduction in the concentration of common proteinases in gastric juice. Adrenoblockers abolished the inhibitor action of ADH on gastric secretion produced by food or humoral irritants, while the inhibitory action of fat was not reversed by phentolamine or obsidan. The data obtained indicate a different mechanism of the inhibitory effect of fat and ADH on gastric secretion.
Experiments were performed on chloralose anaesthetized cats. Biliary and pancreatic secretions were diverted by separate cannulation of each duct. A 2-cm segment of the proximal duodenum was isolated between two luminally situated balloons and perfused with isotonic saline containing 14C-PEG 4000 as a non-absorbable marker. The perfusate was analysed with regard to alkalinity (back titration) and concentration of marker (liquid scintillation). Net alkalinization and net fluid transport were calculated with conventional equations. Motor activity in the duodenal wall was recorded as changes in volume of the proximal balloon. Exposing the duodenal segment of 30 mM HCl induced duodenal contractions, net fluid secretion and an increased alkaline secretion, responses which were insensitive to acute truncal vagotomy. The acid-induced increase in contraction frequency was inhibited by hexamethonium, but not by atropine. Alkaline secretion in response to luminal acid was blocked by hexamethonium and inhibited by atropine, whereas the net fluid secretion was insensitive to these compounds. It is concluded that luminal exposure to hydrochloric acid changes the duodenal functional state by mechanisms which are independent of the extrinsic neural supply. Duodenal contractions during luminal acid exposure, and the alkalinization after such acid exposure, are mediated via local neural pathways, involving a nicotinic cholinergic step and, to some degree, muscarinic transmission. The mucosal volume secretion, however, appears to be mediated by non-conventional mechanisms.
OBJECTIVE: To determine whether acid instillation augments tumor necrosis factor-alpha and nitric oxide production by alveolar macrophages in rats, and to study the effects of treatment with pentoxifylline before acid instillation on the production of these inflammatory mediators. DESIGN: Controlled laboratory investigation on tumor necrosis factor-alpha and nitric oxide production by alveolar macrophages of rats that had acid-induced lung injury. SETTING: University research laboratory. SUBJECT: Alveolar macrophages of rats. INTERVENTIONS: Alveolar macrophages were recovered by bronchoalveolar lavage at 4, 10, 16, 24, and 72 hrs after unilateral hydrochloric acid (pH, 1.0; volume, 0.1 mL) instillation into the lungs of rats. Alveolar macrophages then were cultured with or without lipopolysaccharide. One group of rats was pretreated with pentoxifylline before acid instillation. MEASUREMENTS AND MAIN RESULTS: Alveolar macrophages from both acid-instilled and contralateral lungs, which had recovered 24 hrs after acid instillation, produced significantly greater tumor necrosis factor-alpha and nitric oxide. Subsequent exposure to lipopolysaccharide, as a surrogate for bacterial infection, further promoted tumor necrosis factor-alpha and nitric oxide release. Alveolar macrophages from rats pretreated with pentoxifylline before acid instillation produced significantly less tumor necrosis factor-alpha and did not overproduce tumor necrosis factor-alpha when exposed to lipopolysaccharide. In contrast, pretreatment with pentoxifylline had no effect on nitric oxide production by alveolar macrophages. CONCLUSIONS: Acid instillation stimulates alveolar macrophages to produce tumor necrosis factor-alpha and nitric oxide. Pentoxifylline preserved innate production of tumor necrosis factor-alpha to lipopolysaccharide and did not inhibit the production of bactericidal nitric oxide. This may partly explain why pentoxifylline reduces acid aspiration-induced lung injury while maintaining the host's ability to combat bacterial infection after acid aspiration.
The effect of intraluminal acid and cholecystokinin (CCK) receptor blockade on the pancreatic secretory response was examined in rats. Blockade of gastric acid secretion by YM022 (CCK-B receptor antagonist) or famotidine (histamine-2 receptor antagonist) resulted in a significant suppression of casein-stimulated pancreatic exocrine secretion as determined by juice volume and amylase secretion. Ligation of the gastric pylorus, which leads to complete prevention of gastric acid from entering the duodenum, also suppressed pancreatic exocrine secretion. FK480 (CCK-A receptor antagonist) inhibited pancreatic exocrine secretion dose dependently at doses of 0.01-1.0 mg/kg. When submaximal doses of FK480 and YM022 were treated concomitantly, pancreatic exocrine secretion was inhibited more profoundly than when treated solely. Hydrochloric acid (HCl; 0.05 N), injected into the duodenum, stimulated pancreatic exocrine secretion to a level comparable to that exhibited by intraduodenal casein. This effect of HCl was inhibited by FK480 (1.0 mg/kg) but not by YM022 (1.0 mg/kg). These findings suggest that inhibition of gastric acid secretion leads to the suppression of pancreatic exocrine secretion through mechanisms mediated by CCK-A receptors.
Sixteen antacids were characterized as well as the milk as regards the acid-bounding properties. The study was carried out via the automatic pH-meter titrigraph (Radiometer--Copenhagen). Quantitative data on the acid-bounding capacity were obtained, as well as on the buffer properties and the duration of the interaction between the drugs studied with the titrating solution of hydrochloric acid. The information from that study could well be useful for our pharmaceutical industry, serving as a base for in vivo studies on antacids and in the therapeutic practice for preparing the therapeutic schedules for ulcer disease.
A 27-year-old man presented to our hospital complaining of multiple mild injuries sustained in an attack of violence at the workplace. He had received chemical burns to the penis induced by hydrochloric acid and had developed severe phimosis. He complained of pain on erection and ballooning during urination. The foreskin was partially resected with foreskin grafting for the stricture. The postoperative outcome was favorable and his symptoms were relieved.
Two cases of corrosive burns of the stomach after the ingestion of acid by children are presented. Both patients were the same sex and of a similar age (19 and 20 months). The chemical nature of the caustic substance ingested (hydrochloric acid) and the lack of initial symptoms were also similar. The clinical diagnosis however, was completely different due to the endoscopic finding of serious gastric lesions in one of the patients which were then treated accordingly. In children, the accidental ingestion of caustic acids is often accompanied by few clinical symptoms initially. This can lead to failure to diagnose correctly when symptoms are correlated with the existence and severity of digestive lesions. When a caustic substance has been ingested, in addition to symptoms, consideration of the acidity or alkalinity of the ingested product is also an important parametre in evaluating endoscopic findings.
INTRODUCTION: Acid, a principal component of refluxate, may contribute to the neoplastic progression of Barrett's esophagus. Brief acid exposure in vivo and in vitro has been shown to increase cell proliferation. The mechanisms underlying the hyperproliferative response are not well elucidated but may include alterations in Na(+)-H+ exchanger activity and MAPK signaling pathways. OBJECTIVE: To ascertain the effects of pulsatile acid exposure on gene expression in a Barrett's adenocarcinoma cell line (SEG-1). METHODS: SEG-1 cells were exposed to either acidified DMEM at pH 3.5 (0.1 M hydrochloric acid) or pH 7.4 (control) for 20 min followed by neutralization of the medium. Total RNA was extracted before acid exposure and over a 10-h time course (0.5, 2, 4, 6, 8, and 10 hours) and hybridized to Affymetrix human U133A oligonucleotide arrays. Data were analyzed using the Affymetrix statistical expression algorithms. Only alterations in gene expression that were > or = 2 and < or = -2 fold were studied further and a subset was further investigated by reverse transcription polymerase chain reaction (RT-PCR) and densitometry. Apoptosis was assayed in SEG-1 cells by western blot for cleaved caspase 3 and an apoptosis ELISA assay. RESULTS: Changes in expression were identified for 138 genes. Analysis of gene function identified immediate downregulation of genes associated with apoptosis and early upregulation of genes associated with proliferation. The gene expression profiles suggest that MAPK pathways may be involved and suppression of apoptosis may occur via p53-dependent mechanisms. CONCLUSIONS: Microarray analysis of gene expression changes in a Barrett's adenocarcinoma cell line has identified cellular pathways that may be disrupted following acid exposure.
Functional dyspepsia can be associated with impaired gastric relaxation in response to food intake and delayed gastric emptying. In this study, we investigated whether luminal hydrochloric acid (HCl) may reproduce these motor alterations in phenobarbital-anaesthetized rats via activation of extrinsic neural pathways. Intragastric pressure (IGP) changes induced by a 2-mL fluid bolus were recorded with an oesophageal catheter, and gastric emptying was determined via the fluid volume recovered from the stomach 30-min post-bolus. Experiments involving acute nerve transections or pharmacological blockade of nitric oxide synthesis revealed that the initial increase of IGP after a 0.35 mol L(-1) HCl bolus is dampened by duodenogastric and gastrogastric relaxation reflexes depending on vagal and splanchnic pathways as well as nitric oxide. Compared with saline, HCl (0.15-0.5 mol L(-1)) delayed the subsequent decrease (adaptation) of IGP, inhibited gastric emptying and stimulated gastric fluid secretion as seen in stomachs with ligated pylorus. The acid-evoked delay in IGP adaptation and inhibition of gastric emptying involved duodenogastric and duodenopyloric extrinsic nerve reflexes, whereas the gastric fluid secretion was independent of the extrinsic innervation. It is proposed that the gastropyloric motor changes induced by luminal acid challenge have a bearing on the motor disturbances underlying functional dyspepsia.
Acid aspiration leads to thromboxane-dependent lung neutrophil sequestration associated with microvascular permeability increase. Leukotriene B4 (LTB4) is postulated to be a cofactor in the thromboxane-induced inflammatory response. This study tests the interaction between LTB4 and thromboxane, focusing on LTB4 induction of thromboxane-dependent lung neutrophil sequestration after acid aspiration. Anesthetized rats underwent tracheostomy and insertion of a cannula in a left lung segment. This was followed by instillation of either 0.1 ml 0.1N hydrochloric acid (n = 18) or 0.1 ml saline in control rats (n = 18). When assayed at 3 hours, acid aspiration led to increased plasma levels of LTB4 and thromboxane B2 (TxB2), higher than control values (p less than 0.05). The rise in plasma LTB4 was correlated (p less than 0.05; r = 0.83) with sequestration of neutrophils in the nonaspirated lung. The entrapment of thromboxane-dependent lung neutrophil was associated with an increase in protein concentration in bronchoalveolar lavage of the aspirated and nonaspirated sides and an increase in lung wet to dry weight ratio. Pretreatment of other rats (n = 18) with the lipoxygenase inhibitor diethylcarbamazine IV prevented an aspiration-induced rise in plasma LTB4 and TxB2. Further, there was an attenuation of lung leukosequestration and protein leak in bronchoalveolar lavage and lung edema (all p less than 0.05). Pretreatment of other rats (n = 12) with the leukotriene receptor antagonist FPL 55712 IV did not prevent the aspiration-induced rise in LTB4 or TxB2, but otherwise was as effective as diethylcarbamazine in preventing injury. Finally, other hydrochloric acid-aspirated rats (n = 8) were pretreated intravenously with the thromboxane synthetase inhibitor OKY 046 or the thromboxane receptor antagonist SQ 29548. Both agents limited the aspiration-induced rise in plasma LTB4 (p less than 0.05). The data indicate that localized acid aspiration induces synthesis of LTB4 and thromboxane A2. Inhibition of either leukotriene or thromboxane will limit PMN adhesion and increased lung permeability.
Enamel microabrasion using hydrochloric acid and pumice is an effective method to remove superficial enamel discoloration. This procedure is used in many dental offices but little is known about how different treatment combinations of hand applicator pressure on the tooth, number of applications, and duration of application affect the amount of enamel loss. This investigation studied variables of time, number of applications, and pressure individually and in combination. Twenty-seven extracted premolars were hand rubbed with an 18% HCL-pumice mixture at time intervals of 5, 10, and 20 sec and 5, 10, and 15 applications under pressures of 10, 20, and 30 g. Fifty-four longitudinal sections were cut from the treated sections and measured for enamel loss (P < 0.05). Enamel loss significantly increased as each variable separately increased. When two variables increased at the same time, a greater amount of enamel loss occurred than when one increased. The combination of 10 ten-sec applications or 15 five-sec applications with 20 g pressure resulted in enamel loss of slightly less than 250 microns.
The study aimed to compare the amounts of softened enamel removable by ultrasonication and by toothbrushing abrasion of briefly eroded samples. Thirty bovine enamel samples were demineralized in hydrochloric acid (pH 2.1) for 60 s and were then either brushed with 350 brushing strokes in toothpaste slurry (group A) or distilled water (group B) or were ultrasonicated for 120 s (group C). Enamel loss was measured after 10, 20, 50 and then after every 50 brushing strokes or after 5, 30, 60 and 120 s ultrasonication. Samples were indented with a Knoop diamond after erosion, and enamel loss due to abrasion or wear was calculated from the change in indentation depth after mechanical treatment. Within- and between-group comparisons were performed by ANOVA or t test. Initially, enamel loss increased with increasing brushing treatment or ultrasonication time. Enamel loss did not increase after 300 brushing strokes in group A (534 +/- 169 nm) or 250 brushing strokes in group B (423 +/- 80 nm), or after 60 s ultrasonication (231 +/- 72 nm). Enamel loss was significantly higher in groups A and B than in group C. The results confirm that ultrasonication removes only the outer, more highly demineralized part of the softened enamel layer. Results also indicate that toothbrushing abrasion removes more softened enamel from briefly eroded enamel than ultrasonication, and therefore probably removes partly demineralized enamel from the deeper part of the softened layer. In vivo, excessive toothbrushing might remove the softened enamel layer almost completely.
Immunoreactive secretin concentrations were measured in femoral venous plasma and in intestinal perfusates during acid and neutral perfusion of small intestinal segments in anesthetized rabbits. Steady-state plasma and luminal secretin concentrations were less than 20 pg/ml. Duodenal perfusion with with 0.1 N hydrochloric acid stimulated peak plasma immunoreactive secretin concentrations of 200 - 300 pg/ml within five minutes. Acid stimulated plasma concentrations remained constant during 30 minutes of perfusion. Secretin output into the acid perfusate (2000 - 4000 pg/min) accompanied the release into plasma. Subsequent perfusion with a neutral solution resulted in a rapid return to steady-state plasma and luminal secretin concentrations. Sequential acid perfusion of the ileum, jejunum, and duodenum stimulated similar concentrations of secretin in plasma and luminal perfusates.
The high incidence of peptic ulcer disease despite decreased acid secretion in the elderly suggests an impairment of mucosal defense mechanism with aging. Stimulation of the intestinal mucosal afferent nerves by intraduodenal application of capsaicin or hydrochloric acid (HCl) increases superior mesenteric artery (SMA) blood flow and protects the duodenal mucosa against deep damage. We tested the hypothesis that the intestinal hyperemia induced by intraduodenal capsaicin or HCL is significantly reduced in older (12 months) rats compared with younger (2 months) rats. Mesenteric blood flow was measured by pulsed Doppler flowmetry in anesthetized rats with the flow probe around the SMA. Two milliliters per kilogram of 160 microM capsaicin or 0.1 N HCl administered intraduodenally increased SMA blood flow significantly in both age groups. The peak response in SMA blood flow, however, was significantly smaller in the older rats than in the younger rats. These observations support the hypothesis that impairment of afferent nerve function occurs with aging in the rat intestine.
A solution of ethyl alcohol, polyethylglycol, and distilled water that did (n = 5) or did not (n = 5) contain 250 micrograms/kg of the calcium channel blocker, nifedipine, was infused into the right atrium in 10 healthy mongrel dogs. Hydrochloric acid (pH = 1.8), 2 ml/kg, was then instilled into both lungs of all dogs via the tracheal tube. Hemodynamic data were collected before and 10 minutes after nifedipine was infused and 10, 45, 90 and 180 minutes after acid was instilled into the lungs. Gas exchange, including PaO2 and venous admixture, did not differ between the two groups. However, after aspiration, oxygen delivery significantly improved in the dogs given nifedipine compared to oxygen delivery in those not treated with nifedipine. We conclude that, despite significant decreases in PaO2 and venous admixture, nifedipine can restore oxygen delivery back to normal levels.