GASTROINTESTINAL MOTILITY IN ELDERLY PATIENTS WITH WELL-CONTROLLED TYPE 2 DIABETES MELLITUS.

BACKGROUND: Gastrointestinal (GI) motility disorders in type 2 diabetes mellitus (T2DM) are common. However, the endpoints in well-controlled T2DM in elderly patients are barely understood. OBJECTIVE: To evaluate GI transit and gastric myoelectric activity in elderly patients with T2DM who were undergoing treatment with metformin and to compare them with non-diabetic healthy controls. METHODS: A total of thirty participants were enrolled in this study: young non-diabetic (n=10), elderly non-diabetic controls (n=10), and patients with T2DM managed with metformin (n=10). After fasting overnight, the participants ingested a standard meal and magnetic markers for non-invasive monitoring of GI transit and gastric contractility using the alternating current biosusceptometry and electrogastrography techniques. RESULTS: Mean gastric emptying time, mean colon arrival time, and mean intestinal transit time were determined. There were no significant differences between the groups and in the parameters evaluated (P>0.05). The frequency and amplitude of gastric myoelectric activity were not different between groups; however, abnormal rhythmic index and the half-bandwidth were slightly higher for both elderly diabetic and non-diabetic groups compared with the young adults (P<0.01 and P<0.05, respectively). CONCLUSION: Our study showed unaltered gastric emptying and intestinal transit in T2DM patients with good glycemic control, and suggest changes in the gastric electrical activity can be a part of aging.

Motilidade gastrintestinal em pacientes idosos com diabetes mellitus tipo 2 bem controlado / Gastrointestinal motility in elderly patients with well-controlled type 2 diabetes mellitus

ABSTRACT Background: Gastrointestinal (GI) motility disorders in type 2 diabetes mellitus (T2DM) are common. However, the endpoints in well-controlled T2DM in elderly patients are barely understood. Objective: To evaluate GI transit and gastric myoelectric activity in elderly patients with T2DM who were undergoing treatment with metformin and to compare them with non-diabetic healthy controls. Methods: A total of thirty participants were enrolled in this study: young non-diabetic (n=10), elderly non-diabetic controls (n=10), and patients with T2DM managed with metformin (n=10). After fasting overnight, the participants ingested a standard meal and magnetic markers for non-invasive monitoring of GI transit and gastric contractility using the alternating current biosusceptometry and electrogastrography techniques. Results: Mean gastric emptying time, mean colon arrival time, and mean intestinal transit time were determined. There were no significant differences between the groups and in the parameters evaluated (P>0.05). The frequency and amplitude of gastric myoelectric activity were not different between groups; however, abnormal rhythmic index and the half-bandwidth were slightly higher for both elderly diabetic and non-diabetic groups compared with the young adults (P<0.01 and P<0.05, respectively). Conclusion: Our study showed unaltered gastric emptying and intestinal transit in T2DM patients with good glycemic control, and suggest changes in the gastric electrical activity can be a part of aging.

RESUMO Contexto: As desordens da motilidade gastrintestinal (GI) no diabetes mellitus tipo 2 (DM2) são comuns. No entanto, os desfechos em pacientes idosos com DM2 bem controlado são pouco compreendidos. Objetivo: Avaliar o trânsito GI e a atividade mioelétrica gástrica em idosos com DM2 em tratamento com metformina e compará-los com controles saudáveis não diabéticos. Métodos: Trinta participantes foram incluídos neste estudo: adultos jovens não diabéticos (n=10), idosos não diabéticos (n=10) e pacientes com DM2 tratados com metformina (n=10). Após jejum noturno, os participantes ingeriram uma refeição padrão e marcadores magnéticos para monitoramento não invasivo do trânsito GI e da contratilidade gástrica usando as técnicas de biosusceptometria de corrente alternada e eletrogastrografia. Resultados: Foram determinados o tempo médio de esvaziamento gástrico, o tempo médio de chegada ao cólon e o tempo médio de trânsito intestinal. Não houve diferenças significativas entre os grupos e nos parâmetros avaliados (P>0,05). A frequência e amplitude da atividade mioelétrica gástrica não foram diferentes entre os grupos; entretanto, o índice rítmico anormal e a meia largura de banda foram ligeiramente maiores para os grupos idosos diabéticos e não diabéticos em comparação com os adultos jovens (P<0,01 e P<0,05, respectivamente). Conclusão: Nosso estudo mostrou esvaziamento gástrico e trânsito intestinal inalterados em pacientes com DM2 com bom controle glicêmico, sugerindo que as alterações na atividade elétrica gástrica podem fazer parte do envelhecimento.

The Influence of Omeprazole on the Dissolution Processes of pH-Dependent Magnetic Tablets Assessed by Pharmacomagnetography.

Pharmacomagnetography involves the simultaneous assessment of solid dosage forms (SDFs) in the human gastrointestinal (GI) tract and the drug plasmatic concentration, using a biomagnetic technique and pharmacokinetics analysis. This multi-instrumental approach helps the evaluation, as GI variables can interfere with the drug delivery processes. This study aimed to employ pharmacomagnetography to evaluate the influence of omeprazole on the drug release and absorption of metronidazole administered orally in magnetic-coated tablets. Magnetic-coated tablets, coated with Eudragit® E-100 (E100) and containing 100 mg of metronidazole, were produced. For the in vivo experiments, 12 volunteers participated in the two phases of the study (placebo and omeprazole) on different days to assess the bioavailability of metronidazole. The results indicated a shift as the pH of the solution increased and a delay in the dissolution of metronidazole, showing that the pH increase interferes with the release processes of tablets coated with E100. Our study reinforced the advantages of pharmacomagnetography as a tool to perform a multi-instrumental correlation analysis of the disintegration process and the bioavailability of drugs.

Gastrointestinal Side Effects of Triple Immunosuppressive Therapy Evaluated by AC Biosusceptometry and Electrogastrography in Rats.

BACKGROUND: Triple immunosuppressive therapy is associated with several gastrointestinal disorders. The aim of this study was to investigate the effects induced by the triple immunosuppressive therapy on the gastrointestinal tract of rats. METHODS: Male Wistar rats were randomly assigned into three experimental groups: Control: filtered water; TAC + MPS + PRED: treated with Tacrolimus plus Mycophenolate Sodium plus Prednisone; and CSA + AZA + PRED: treated with Cyclosporine plus Azathioprine plus Prednisone. The treatment was done for 14 days by gavage. Gastric emptying and contractility were evaluated by the Alternating Current Biosusceptometry (ACB) and Electrogastrography (EGG). Histological, biochemical and hematological analyses were also performed. RESULTS: Gastric emptying time was slower in the CSA + AZA + PRED group in comparison with control (p<0.01) and TAC + MPS + PRED groups (p<0.001). Animals treated with TAC + MPS + PRED showed accelerated gastric emptying (p<0.05) compared to control. The amplitude of gastric contractions in both immunosuppressed groups was higher than observed in the control. The frequency of gastric contractions for the CSA + AZA + PRED group was also increased (p<0.01). Results obtained by EGG were similar to those recorded with the ACB. The thickness of the circular layer from stomach muscle decreased in both immunosuppressed groups, while the longitudinal layer was reduced only in the CSA + AZA + PRED group. CONCLUSION: Triple immunosuppressive therapy alters gastric motility, compromises the muscular layers and the association between CSA, AZA, and PRED provokes the major alterations in the structure and gastric function. Specific gastrointestinal side effects resulting from different immunosuppressive therapies still need to be elucidated in order to provide more effective and personalized therapy for patients.

Gastrointestinal effects of ivermectin treatment in rats infected with Strongyloides venezuelensis.

We aimed to evaluate the effects of ivermectin treatment on gastrointestinal morphology and function after Strongyloides venezuelensis infection. Male rats composed Control (C), Parasitized (Sv), Ivermectin (IVM) and Parasitized and treated with Ivermectin (Sv/IVM) groups. IVM and Sv/IVM groups were subdivided according to IVM: single dose of 200 µg/kg (IVM1 and Sv/IVM1) or three repeated doses of 200 µg/kg at 24 h intervals (IVM3 and Sv/IVM3). First dose of IVM was administered after peak of infection. Eggs per gram (EPG), mean gastric emptying time (MGET), mean cecum arrival time (MCAT) and mean small intestinal transit time (MSITT) were evaluated. Measurements were performed before drug and at peak of infection, first day post peak of infection and 30 days post infection. Same time intervals were simulated for uninfected animals. Number of recovered worms and intestinal morphometry were also rated. Data were analyzed by ANOVA and correlated by Dunnett and Pearson (p < 0.05). Sv/IVM1 and Sv/IVM3 showed reduction of EPG and worms, although only group SV/IVM3 eradicate them. Hastened gastric emptying and slowed intestinal transit provoked by S. venezuelensis infection can be reverted by a single administration of IVM after peak of infection, even without total parasite elimination. Although three consecutive doses of IVM were more efficient to eradicate the parasite, drug administration impaired gastrointestinal function and morphology. IVM alone affected gastrointestinal parameters in uninfected animals for prolonged periods, especially in high doses. In control, there were strong negative correlations between MSITT and muscle layers. Strongyloides venezuelensis infection abolishes such correlations. Longitudinal muscle was thinner in IVM3 and Sv/IVM3 groups and circular thicker in Sv group. Revisiting the action of traditional drugs broadens knowledge in the parasite-host interface and may result in the development of more accurate therapeutic strategies.

Mild diabetes: long-term effects on gastric motility evaluated in rats.

Moderate hyperglycaemic levels seem to be related to abnormal gastric motility in diabetes mellitus. However, experimental models designed to evaluate the relationship between motility and diabetes over time are not yet well established. Our objective was to investigate the long-term effects of mild diabetes on gastric motility in rats. Newborn male rats received streptozotocin (mild diabetes groups - MD) or vehicle (control groups - C), and both groups were evaluated after 3 (C3 and MD3) and 6 months (C6 and MD6) postinduction. Mild diabetic animals (MD3 and MD6) showed moderately elevated blood glucose and decreased insulin levels compared with control (C3 and C6). Insulin secretion was enhanced in MD6 compared with MD3, most likely due to partial ß-cell regeneration indicated by HOMA-ß. In HOMA-IR, it was noticed that MD6 animals had impaired insulin response compared with MD3. Gastric emptying was faster, amplitude of contraction was stronger in MD6 compared with MD3, and in both groups, the differences were significant when compared with control animals. A significant abnormal rhythmic index was calculated for the mild diabetic groups, despite unchanged mean frequency of contraction. In conclusion, despite increased insulin levels over time, constant levels of moderate hyperglycaemia are also related to abnormal gastric motility and impairment of gastric function.

Influence of post-transplant immunosuppressive therapy on gastrointestinal transit using biomagnetic method: a pilot study.

BACKGROUND: Immunosuppressive therapy after kidney transplant is necessary to prevent allograft rejection and it is the cause of several gastrointestinal (GI) disorders that have been scantily studied. OBJECTIVES: This study was aimed at investigating the influence of triple immunosuppressive therapy on GI transit in renal transplant patients by employing a biomagnetic technique. METHODS: Twenty-one renal transplant patients underwent triple therapy, which included either tacrolimus (TAC) or cyclosporin A (CsA) associated with prednisone and azathioprine. They were all evaluated, and fifteen other healthy individuals formed the control group. After a standardized meal, GI transit of magnetic markers was assessed using Alternating Current Biosusceptometry (ACB). RESULTS: Patients taking TAC had significantly accelerated gastric emptying and colonic arrival (p ≤ 0.001) when compared with those taking CsA and those in the control group. However, no differences were observed in small bowel transit among the groups studied. Overall, the inter-subject coefficients of variation for gastrointestinal transit parameters were higher for the TAC group and similar for the CsA and control groups. CONCLUSION: This study demonstrated that ACB is a suitable methodology when evaluating the influence of different immunosuppressive therapies on gastrointestinal transit after renal transplantation. Pronounced inter-individual variation was found in patients treated with tacrolimus, thus showing the prokinetic effect of this drug on GI motility. Studies of motility patterns in this population could be useful as complementary information toward determining the mechanisms and the relationship between motility and therapeutic doses.

Different patterns between mechanical and electrical activities: an approach to investigate gastric motility in a model of long-term diabetic rats.

The relationship between time-courses of mechanical and electrical events in longstanding diabetes was investigated in rats. Magnetic markers and electrodes were surgically implanted in the gastric serosa of male rats. Simultaneous recordings were obtained by AC biosusceptometry, electromyography and electrogastrography one, three and six months after injections of saline (control) or alloxan (diabetic). Frequency and amplitude of contraction, abnormal rhythmic index and half-bandwidth were obtained (ANOVA P < 0.05). Antral hypomotility and gastric motility instability were observed in the signal waveform of diabetic rats at the three time points of study. The mean frequency (4.4 ± 0.4 cpm) was strictly similar, but the mechanical and electrical correlation was lowest for diabetics groups. Decreases in mechanical amplitude were observed for all diabetic groups compared with control; also the ranges of frequency were much wider in diabetes. The half-bandwidth increased since the first month in mechanical recordings and only after the third month in electrical. In diabetic animals, about 40% of gastric activity was abnormal (against 12% in control) and may reach 60% in the sixth month of mechanical recordings. The multi-instrumental approach showed a more substantial deterioration in mechanical activity and created an integrative view of gastric motility for longstanding diabetic model.

Development of an AMR-ACB array for gastrointestinal motility studies.

The association between anisotropic magnetoresistive (AMR) sensor and AC biosusceptometry (ACB) to evaluate gastrointestinal motility is presented. The AMR-ACB system was successfully characterized in a bench-top study, and in vivo results were compared with those obtained by means of simultaneous manometry. Both AMR-ACB and manometry techniques presented high temporal cross correlation between the two periodicals signals . The contraction frequencies using AMR-ACB were 73.9 ± 7.6 mHz and using manometry were 73.8 ± 7.9 mHz during the baseline . The amplitude of contraction using AMR-ACB was 396 ± 108 µT·s and using manometry were 540 ± 198 mmHg·s during the baseline. The amplitudes of signals for AMR-ACB and manometric recordings were similarly increased to 86.4% and 89.3% by neostigmine, and also decreased to 27.2% and 21.4% by hyoscine butylbromide in all animals, respectively. The AMR-ACB array is nonexpensive, portable, and has high-spatiotemporal resolution to provide helpful information about gastrointestinal tract.

Employment of a noninvasive magnetic method for evaluation of gastrointestinal transit in rats.

AC Biosusceptometry (ACB) was previously employed towards recording gastrointestinal motility. Our data show a reliable and successful evaluation of gastrointestinal transit of liquid and solid meals in rats, considering the methods scarcity and number of experiments needed to endorsement of drugs and medicinal plants. ACB permits real time and simultaneous experiments using the same animal, preserving the physiological conditions employing both meals with simplicity and accuracy.

Biomagnetic methods: technologies applied to pharmaceutical research.

Biomagnetic methods have been designed for a wide range of applications. Recently, such methods have been proposed as alternatives to scintigraphy for evaluating of a number of pharmaceutical processes in vitro as well as under the influence of gastrointestinal physiological parameters. In this review, physical characterization as well as the most recent applications of Superconducting Quantum Interference Device (SQUID), Anisotropic Magnetoresistive (AMR) and AC Biosusceptometry (ACB) in the pharmaceutical research will be explored. Moreover, their current status and how these technologies can be employed to improve the knowledge about the impact of gastrointestinal physiology on drug delivery in association with pharmacokinetic outcomes, termed pharmacomagnetography, will be presented.

Effects of meal size and proximal-distal segmentation on gastric activity.

AIM: To evaluate the effects of meal size and three segmentations on intragastric distribution of the meal and gastric motility, by scintigraphy. METHODS: Twelve healthy volunteers were randomly assessed, twice, by scintigraphy. The test meal consisted of 60 or 180 mL of yogurt labeled with 64 MBq (99m)Tc-tin colloid. Anterior and posterior dynamic frames were simultaneously acquired for 18 min and all data were analyzed in MatLab. Three proximal-distal segmentations using regions of interest were adopted for both meals. RESULTS: Intragastric distribution of the meal between the proximal and distal compartments was strongly influenced by the way in which the stomach was divided, showing greater proximal retention after the 180 mL. An important finding was that both dominant frequencies (1 and 3 cpm) were simultaneously recorded in the proximal and distal stomach; however, the power ratio of those dominant frequencies varied in agreement with the segmentation adopted and was independent of the meal size. CONCLUSION: It was possible to simultaneously evaluate the static intragastric distribution and phasic contractility from the same recording using our scintigraphic approach.

AC Biosusceptometry as a method for measuring gastric contraction.

The aim of this study was to validate the alternate current biosusceptometry (ACB) for monitoring gastric contractions in rats. In vitro data were obtained to establish the relationship between ACB and the strain-gauge (SG) signal amplitude. In vivo experiments were performed on rats with magnetic markers and SGs previously implanted under the gastric serosa. The effects of the prandial state in gastric motility profiles were obtained. The correlation between in vitro signal amplitudes was strong (R = 0.989). The temporal cross-correlation between the ACB and SG signal amplitude was higher in the postprandial than in the fasting state. Irregular signal profiles, low contraction amplitudes, and smaller signal-to-noise ratios explained the poor correlation for fasting-state recordings. The contraction frequencies using ACB were 0.068 ± 0.007 Hz (postprandial) and 0.058 ± 0.007 Hz (fasting) and those using SG were 0.066 ± 0.006 Hz (postprandial) and 0.059 ± 0.008 Hz (fasting) (P < 0.003). When a magnetic tracer was ingested, there was a strong correlation and a small phase-difference between techniques. We conclude that ACB provides an accurate and sensitive technique for studies of GI motility in the rat.

The ACB technique: a biomagentic tool for monitoring gastrointestinal contraction directly from smooth muscle in dogs.

The aim of this paper was to verify whether AC biosusceptometry (ACB) is suitable for monitoring gastrointestinal (GI) contraction directly from smooth muscle in dogs, comparing with electrical recordings simultaneously. All experiments were performed in dogs with magnetic markers implanted under the serosa of the right colon and distal stomach, and their movements were recorded by ACB. Monopolar electrodes were implanted close to the magnetic markers and their electric potentials were recorded by electromyography (EMG). The effects of neostigmine, hyoscine butylbromide and meal on gastric and colonic parameters were studied. The ACB signal from the distal stomach was very similar to EMG; in the colonic recordings, however, within the same low-frequency band, ACB and EMG signals were characterized by simultaneity or a widely changeable frequency profile with time. ACB recordings were capable of demonstrating the changes in gastric and colonic motility determined by pharmacological interventions as well as by feeding. Our results reinforce the importance of evaluating the mechanical and electrical components of motility and show a temporal association between them. ACB and EMG are complementary for studying motility, with special emphasis on the colon. ACB offers an accurate method for monitoring in vivo GI motility.

AC biosusceptometry technique to evaluate the gastrointestinal transit of pellets under influence of prandial state.

Multiparticulate dosage forms have been proposed when distal regions of gastrointestinal tract are desirable as target of drugs. It is known that physiological parameters might interfere with the processes related to the drug delivery and absorption and therefore, it is essential to evaluate the behavior of such delivery systems in vivo. The aim of this study was to propose the AC Biosusceptometry technique as a noninvasive and radiation free device to evaluate the gastrointestinal transit of a magnetic multiparticulate dosage form in healthy volunteers under fasting and fed conditions. Magnetic pellets were prepared by the powder layering method of ferrite on nonpareils sugar beads and coated by using Eudragit. Our data showed that the AC Biosusceptometry technique was able to monitoring the gastrointestinal transit of pellets presenting similar profiles as demonstrated by standard techniques. Food intake has markedly influenced the gastric emptying as well as the colon arrival and the small intestine transit of magnetic pellets.

Pharmaceutical applications of AC biosusceptometry.

AC Biosusceptometry offers an alternative to investigate noninvasively and without ionizing radiation the behavior of solid dosage forms in vitro and in the human gastrointestinal tract. This versatility allowed applying this technique in a wide field ranging from characterization of the disintegration process to elucidation of how the physiological parameters can interfere with pharmaceutical processes. It is increasingly important to understand how oral solid dosage forms behave in the human gastrointestinal tract. Once labelled, magnetic dosage forms provide an excellent opportunity to investigate complexes' interactions between dosage form and gastrointestinal physiology. In this paper, basic principles of this biomagnetic instrumentation and of the quantification based on magnetic images are reviewed. Also will be presented are some of the most recent applications of AC Biosusceptometry in the pharmaceutical research including oesophageal transit, gastric emptying and transit time of multiparticulate dosage forms, hydrophilic matrices and disintegration of tablets.

Electrical and mechanical effects of hyoscine butylbromide on the human stomach: a non-invasive approach.

Due to the importance of motility in a number of gastrointestinal disorders, efforts have been made to evaluate both gastric motility counterparts: electrical activity and mechanical activity. The present work aimed to propose a new approach, associating AC biosusceptometry (ACB) and electrogastrography (EGG), to noninvasively monitoring mechanical and electrical gastric activity, respectively. Fourteen volunteers ingested a test meal and their gastric activity was evaluated by EGG and ACB at a baseline and after 20 mg of i.v. hyoscine butylbromide. ACB and EGG showed a similar signal pattern and high temporal correlation. Hyoscine butylbromide decreased the mechanical motility index (MI) by 50.9%, while for electrical MI the reduction was 36.5%. Delayed times to onset (mean+/-SD: 50+/-15 versus 40+/-20 s; P<0.01) and the inhibitory effect (16+/-4 versus 14+/-5 min; P<0.01) were calculated for ACB and EGG, respectively. ACB and EGG emerged due to their interesting nature, noninvasiveness and low cost to evaluate gastric motility. Our approach associating ACB and EGG allowed monitoring and quantification of the effects of an anticholinergic drug in gastric electrical activity and contractile activity in humans.

Gastric motility evaluated by electrogastrography and alternating current biosusceptometry in dogs.

Association techniques could be the answer for evaluating electromechanical coupling and gastric emptying under basal conditions and after administration of drugs. Electrogastrography (EGG) and alternating current biosusceptometry (ACB) emerged due to their interesting nature, noninvasiveness and low cost. The aims were to examine in dogs the effect of erythromycin on gastric emptying by ACB and electrical and motor responses to erythromycin and propranolol by ACB and EGG respectively. Twelve beagle dogs ingested a solid test meal on separate days. Under anesthesia, gastric motility was evaluated by EGG and ACB after erythromycin and propranolol administration. Without anesthesia, gastric emptying was assessed under basal conditions and after erythromycin by ACB. ACB and EGG showed a strong temporal correlation. Erythromycin and propranolol presented the same profile with different power ratios; the amplitude increased whereas frequency decreased. Also, erythromycin administration hastened gastric emptying while reducing the orocaecal transit time. There is a demand for reliable, easy-to-perform and comfortable techniques to record gastric emptying and gastric activity in medicine and veterinary practice. In summary, the association of ACB with EGG accompanied by an appropriate animal model is promising for evaluating effects of drugs in gastric myoelectrical and contractile activity.

Influence of compression forces on tablets disintegration by AC Biosusceptometry.

Analysis of physical phenomena that occurs during tablet disintegration has been studied by several experimental approaches; however none of them satisfactorily describe this process. The aim of this study was to investigate the influence of compression force on the tablets by associating the AC Biosusceptometry with consolidated methods in order to validate the biomagnetic technique as a tool for quality control in pharmaceutical processes. Tablets obtained at five compression levels were submitted to mechanical properties tests. For uncoated tablets, water uptake and disintegration force measurements were performed in order to compare with magnetic data. For coated tablets, magnetic measurements were carried out to establish a relationship between physical parameters of the disintegration process. According to the results, differences between the compression levels were found for water uptake, force development and magnetic area variation measurements. ACB method was able to estimate the disintegration properties as well as the kinetics of disintegration process for uncoated and coated tablets. This study provided a new approach for in vitro investigation and validated this biomagnetic technique as a tool for quality control for pharmaceutical industry. Moreover, using ACB will also be possible to test these parameters in humans allowing to establish an in vitro/in vivo correlation (IVIVC).

A novel biomagnetic instrumentation with four magnetoresistive sensors to evaluate gastric motility.

A novel instrumentation using anisotropic magnetoresistive (AMR) sensors associated with magnetic coils excitation was developed to evaluate gastrointestinal tract motility parameters. The susceptometer has four sensors that were used to measure the gastric activity contractions (GAC) in anaesthetized dogs, its performance was evaluated by manometry with good results.