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PubMed1989

Thyroid hormones modulate thyrotropin-releasing hormone biosynthesis in tissues outside the hypothalamic-pituitary axis of male rats.

In the present study we have examined the in vivo effects of thyroid hormone and TRH on secretory tissue concentrations of TRH and TRH-Gly (pGlu-His-Pro-Gly), a TRH precursor. Within secretory granules, TRH-Gly is converted to TRH through alpha-amidation of the C-terminal proline residue, using Gly as the NH2 donor. Using specific RIA, we measured the TRH-Gly immunoreactivity (TRH-Gly-IR) and TRH-IR concentrations in tissues from the reproductive and gastrointestinal systems, adrenals, and other internal organs in euthyroid, hypothyroid, and T4-treated 250-g Sprague-Dawley male rats. TRH-Gly-IR concentrations were more than 2-fold higher than TRH-IR concentrations within the adrenal, pancreas, bowel, and stomach at the time of death. Untreated hypothyroidism and exogenous TRH significantly increased adrenal TRH-Gly-IR levels. Pancreatic TRH-Gly levels increased about 2-fold in hypothyroid rats. Incubation at 60 C significantly increased TRH-Gly-IR levels in the pancreas, adrenal, bowel, stomach, and epididymis by 14-, 3-, 6-, 6-, and 6-fold, respectively. Also after 60 C incubation increases in the TRH-Gly-IR/TRH-IR ratio of 2.7-, 4-, and 1.7-fold were observed in the pancreas, epididymis, and bowel, respectively. Pooled tissue extracts were fractionated by cation exchange and reverse phase HPLC for characterization of TRH-Gly-IR. Both chromatographic methods revealed a major peak of TRH-Gly-IR coeluting with synthetic TRH-Gly. Incubation at 60 C caused 13.5-, 4.1-, 1.5-, and 5-fold increments in the TRH-Gly-IR for adrenal, pancreas, prostate, and thyroid, respectively, compared to the immediately extracted control aliquots. Cation exchange and reverse phase HPLC also revealed production of higher mol wt TRH precursor peptides after incubation at 60 C for 4 or 20 h. Only the TRH-Gly-IR peak coeluting with pGlu-His-Pro-Gly was converted into TRH by rat brain alpha-amidating enzyme. The data suggest that biosynthesis of TRH occurs in rat extrahypothalamic tissues and may be modulated by thyroid status, iv TRH, and selective thermal inactivation of enzymes that convert prepro-TRH to TRH.

Adrenal Glands↗

PubMed1993

Aggregation chimeras demonstrate that the primary defect responsible for aganglionic megacolon in lethal spotted mice is not neuroblast autonomous.

The lethal spotted (ls) mouse has been used as a model for the human disorder Hirschsprung's disease, because as in the latter condition, ls/ls homozygotes are born without ganglion cells in their terminal colons and, without surgical intervention, die early as a consequence of intestinal obstruction. Previous studies have led to the conclusion that hereditary aganglionosis in ls/ls mice occurs because neural crest-derived enteric neuroblasts fail to colonize the distal large intestine during embryogenesis, perhaps due to a primary defect in non-neuroblastic mesenchyme rather than migrating neuroblasts themselves. In this investigation, the latter issue was addressed directly, in vivo, by comparing the distributions of ls/ls and wild-type neurons in aggregation chimeras. Expression of a transgene, D beta H-nlacZ, in enteric neurons derived from the vagal neural crest, was used as a marker for ls/ls enteric neurons in chimeric mice. In these animals, when greater than 20% of the cells were wild-type, the ls/ls phenotype was rescued; such mice were neither spotted nor aganglionic. In addition, these 'rescued' mice had mixtures of ls/ls and wild-type neurons throughout their gastrointestinal systems including distal rectum. In contrast, mice with smaller relative numbers of wild-type cells exhibited the classic ls/ls phenotype. The aganglionic terminal bowel of the latter mice contained neither ls/ls nor wild-type neurons. These results confirm that the primary defect in ls/ls embryos is not autonomous to enteric neuroblasts, but instead exists in the non-neuroblastic mesenchyme of the large intestine.

Animals↗

PubMed1994

Mesenchymal regulation of epithelial gene expression in developing avian stomach: 5'-flanking region of pepsinogen gene can mediate mesenchymal influence on its expression.

The expression of a gene encoding an embryonic chick pepsinogen was investigated in developing avian gut. Expression is restricted to the epithelial layer of the embryonic proventriculus (glandular stomach). We can therefore regard this gene as a marker gene for proventricular epithelial differentiation. There is some considerable evidence in favour of epithelial-mesenchymal interactions being important during the development of the gastrointestinal system; for example, pepsinogen expression is induced in proventricular and gizzard (muscular stomach) epithelial by the proventricular mesenchyme but is suppressed by the gizzard mesenchyme. In the present paper, we studied how the mesenchymes influence this gene expression pattern. For this we produced constructs containing various portions of the 5'-flanking region of the embryonic chick pepsinogen gene, driving reporter sequences (beta-galactocidase or luciferase), and these constructs were transfected into dissociated epithelial cells either from the proventriculus or gizzard. We then recombined these cells with mesenchymal cells and cultured them as cell aggregates. In this way, we were able to dissect the timing and other requirements of the epithelial-mesenchymal interactions for expression of embryonic chick pepsinogen gene. We also report that 1.1 kb of 5'-flanking sequence is sufficient to drive correct expression of embryonic chick pepsinogen gene, although further enhancement was seen if the constructs contained 3.2 kb of upstream sequence.

Animals↗

PubMed2001

Autonomic control of heart rate during forced activity and digestion in the snake Boa constrictor.

Reptiles, particularly snakes, exhibit large and quantitatively similar increments in metabolic rate during muscular exercise and following a meal, when they are apparently inactive. The cardiovascular responses are similar during these two states, but the underlying autonomic control of the heart remains unknown. We describe both adrenergic and cholinergic tonus on the heart during rest, during enforced activity and during digestion (24-36 h after ingestion of 30 % of their body mass) in the snake Boa constrictor. The snakes were equipped with an arterial catheter for measurements of blood pressure and heart rate, and autonomic tonus was determined following infusion of the beta-adrenergic antagonist propranolol (3 mg kg(-1)) and the muscarinic cholinoceptor antagonist atropine (3 mg kg(-1)). The mean heart rate of fasting animals at rest was 26.4+/-1.4 min(-1), and this increased to 36.1+/-1.4 min(-1) (means +/- S.E.M.; N=8) following double autonomic block (atropine and propranolol). The calculated cholinergic and adrenergic tones were 60.1+/-9.3 % and 19.8+/-2.2 %, respectively. Heart rate increased to 61.4+/-1.5 min(-1) during enforced activity, and this response was significantly reduced by propranolol (maximum values of 35.8+/-1.6 min(-1)), but unaffected by atropine. The cholinergic and adrenergic tones were 2.6+/-2.2 and 41.3+/-1.9 % during activity, respectively. Double autonomic block virtually abolished tachycardia associated with enforced activity (heart rate increased significantly from 36.1+/-1.4 to 37.6+/-1.3 min(-1)), indicating that non-adrenergic, non-cholinergic effectors are not involved in regulating heart rate during activity. Blood pressure also increased during activity. Digestion was accompanied by an increase in heart rate from 25.6+/-1.3 to 47.7+/-2.2 min(-1) (N=8). In these animals, heart rate decreased to 44.2+/-2.7 min(-1) following propranolol infusion and increased to 53.9+/-1.8 min(-1) after infusion of atropine, resulting in small cholinergic and adrenergic tones (6.0+/-3.5 and 11.1+/-1.1 %, respectively). The heart rate of digesting snakes was 47.0+/-1.0 min(-1) after double autonomic blockade, which is significantly higher than the value of 36.1+/-1.4 min(-1) in double-blocked fasting animals at rest. Therefore, it appears that some other factor exerts a positive chronotropic effect during digestion, and we propose that this factor may be a circulating regulatory peptide, possibly liberated from the gastrointestinal system in response to the presence of food.

Adrenergic beta-Antagonists↗

PubMed2000

New anti-inflammatory treatment strategy in Alzheimer's disease.

Numerous reports have indicated that patients suffering from inflammatory diseases (e.g., arthritis) who take anti-inflammatory medication have a reduced risk of developing Alzheimer's disease (AD). Thus, the first generation of anti-inflammatory cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, have been tested as potential therapeutics in AD. Because the inhibition of COX-1 is also known to cause tissue damage in the gastrointestinal system from the resultant reduced cytoprotection, selective COX-2 inhibitors are being investigated and tested clinically as potentially better therapeutics for AD patients. However, such drugs may also trigger unwanted effects; for example, the COX-2 inhibitors, which reduce the production of one type of eicosanoids, the prostaglandins, may increase the production of other eicosanoids; i.e., the leukotriene B4 (LTB4), which is one of the most potent endogenous chemotactic/inflammatory factors. LTB4 production is initiated by the enzyme 5-lipoxygenase (5-LOX). The expression of the 5-LOX gene is upregulated during neurodegeneration and with aging. In spite of the fact that 5-LOX and leukotrienes are major players in the inflammation cascade, their role in AD pathobiology/therapy has not been extensively investigated. We propose that the 5-LOX inflammatory cascade may take part in the process of aging-associated neurodegenerative diseases, and we point to the role of 5-LOX in neurodegeneration and discuss its relevance for anti-inflammatory therapy of AD.

Alzheimer Disease↗

PubMed1999

[Allylnitrile-induced behavioral abnormalities and findings relating to the mechanism underlying behavioral abnormalities].

Nitriles are widely used in industry as plastics, solvents, and synthetic intermediates. It has been shown that the thermal degradation of acrylonitrile-based plastics leads to the emission of a great variety of nitriles. Exposure of humans and experimental animals to some nitriles has been shown to lead to disorders of the central nervous, hepatic, cardiovascular, renal, and gastrointestinal systems. Iminodipropionitrile has long been known to induce in experimental animals behavioral syndromes that other nitriles have not been reported to induce. Recently, we have found that a single administration of allylnitrile, an analog of acrylonitrile, induces in rodents behavioral abnormalities including head twitching, head weaving, random circling, increased locomotor activity, backward pedaling, pivoting, and somersaulting. The induced abnormalities were persistent. Crotononitrile and 2-pentenenitrile also are able to produce behavioral abnormalities. Thus, the nitriles appear as a new class of neurotoxic compounds with potential relevance to the human health. The mechanism by which allylnitrile induces and maintains the behavioral abnormalities is summarised below. 1. Allylnitrile activates the serotonin (5-HT) system in the central nervous system, and as a consequence activation of 5-HT-2 receptors due to increased 5-HT may lead to induction of head twitching. 2. Although the data available indicate that the dopamine (DA) system may be involved in allylnitrile-induced behavioral abnormalities, it remains unknown how the DA system relates to the abnormalities. 3. Allylnitrile decreases the noradrenaline level in the central nervous system, which is thought to be secondary to the 5-HT system activation mentioned above. The allylnitrile-induced head twitching, however, may occur in consequence to both enhanced beta-adrenoceptor stimulation and to the removal of tonic inhibitory control by alpha-2-adrenoceptors. 4. The neuropathological data indicate an important role of the medial habenular and raphe nuclei in allylnitrile-induced behavioral abnormalities. Onset of the behavioral abnormalities appears to be associated with the impairment in the medial habenulo-raphe relay owing to activation of apoptotic cascade in neurons. 5. On the basis of the findings with iminodipropionitrile and crotononitrile, allylnitrile might produce pathological changes in the vestibular sensory hair cells. Further studies are needed to explore the mechanism underlying the allylnitrile-induced syndromes.

Animals↗

PubMed2002

Cadmium exposure and nephropathy in a 28-year-old female metals worker.

A 28-year-old female presented for evaluation of left flank pain and polyuria after having been exposed to cadmium in the jewelry manufacturing industry for approximately 3 years. This patient possessed both elevated 24-hr urinary ss2-microglobulin and elevated blood cadmium levels. Approximately 6 months after initial presentation, the patient resigned from her job due to shortness of breath, chest pain, and anxiety. Exposure to cadmium in the jewelry industry is a significant source of occupational cadmium exposure. Other occupational sources include the manufacture of nickel-cadmium batteries, metal plating, zinc and lead refining, smelting of cadmium and lead, and production of plastics. Cadmium is also an environmental pollutant that accumulates in leafy vegetables and plants, including tobacco. Major toxicities anticipated from cadmium exposure involve the renal, pulmonary, and, to a lesser extent, gastrointestinal systems. These include the development of renal proximal tubular dysfunction, glomerular damage with progressive renal disease, and respiratory symptoms including pneumonitis and emphysema. Low-level cadmium exposure has also been associated with increased urinary calcium excretion and direct bone toxicity, effects that recent research suggests may result in the development of osteoporosis. The body burden of cadmium, over half of which may reside in the kidneys, is most often measured through the use of urinary cadmium levels. Blood cadmium measurements generally reflect current or recent exposure and are especially useful in cases with a short exposure period and only minimal accumulation of cadmium in the kidneys. Both ss2-microglobulin and alpha1-microglobulin serve as organ-specific, early-effect biomarkers of tubular proteinuria and thus play a role in identifying early signs of cadmium-induced renal damage in those with potential exposures. In addition to ensuring workplace compliance with Occupational Safety and Health Administration-mandated monitoring and screening measures, it is prudent for those with cadmium exposure to maintain adequate intake of both iron and calcium, appropriate measures even in the absence of exposure.

Adult↗

PubMed2006

Nutrition and the ostomate: input, output and absorption.

This article discusses the function of the gastrointestinal system in relation to diet and fluid absorption and how this will alter after the formation of a stoma. The different types of stoma are discussed to enable the community nurse to understand how this may lead to changes in dietary requirements for the ostomate (a person with a stoma). The function of the nutrients in the diet is discussed and how the ostomate can best obtain these into their diet.

Colostomy↗

PubMed2002

Absorption of colesevelam hydrochloride in healthy volunteers.

OBJECTIVE: To assess whether colesevelam hydrochloride is absorbed in healthy volunteers. METHODS: A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.9 g twice daily for 4 weeks, followed by a single dose of [14C]-colesevelam 2.4 g (480 pCi). These subjects continued to receive non-radioactive colesevelam 1.9 g twice daily for 4 days after administration of the radiolabeled dose. Blood, urine, and feces were collected immediately prior to administration of [14C]-colesevelam and at specified intervals after administration. The whole-blood equivalent concentration of colesevelam was calculated using data collected throughout the 96 hours following radiolabeled drug administration. The proportion of [14C]-colesevelam excreted through urine or feces was calculated based on the amount of radioactivity recovered up to 216 hours after the radiolabeled dose. RESULTS: The mean cumulative total recovery of [14C]-colesevelam in urine and feces was 0.05% and 74%, respectively. Excluding 2 subjects for whom cumulative recovery was <25%, the mean cumulative fecal recovery was 82%. The mean maximum whole-blood equivalent concentration of colesevelam was 0.165+/-0.10 microg equiv/g 72 hours after administration of [14C]-colesevelam, which was estimated to be 0.04% of the administered dose. All blood samples contained <4 times the number of background counts (dpm). CONCLUSIONS: The cumulative recovery data in urine and feces are consistent with the conclusion that colesevelam is not absorbed and is excreted entirely through the gastrointestinal system.

Allylamine↗

PubMed2004

Advances in management of malignant diseases with the combination of radiation therapy and chemotherapy. Highlights from the 45th Annual Meeting of the American Society for Therapeutic Radiology and Oncology.

From October 19 through October 24, 2003, the American Society for Therapeutic Radiology and Oncology held its 45th Annual Meeting in Salt Lake City, Utah. The meeting was devoted to the presentation of advances in the management of malignant diseases with radiation modalities. The meeting brought together investigators, clinicians, policy makers and professionals interested in the science and impact of radiation on cancerous disease. This report examines the advances in combined modality approaches (i.e., the use of radiation therapy and chemotherapy) for the treatment of malignant disease. The American Society for Therapeutic Radiology and Oncology sponsors an annual meeting devoted to the presentation of radiation-related advances in malignant disorders. The educational elements of this program are targeted at oncologists of all disciplines (i.e., surgical oncologists, medical oncologists, radiation oncologists), physicists, biologists, nurses, and therapists as well as all health care workers who are involved in the treatment of patients with malignant diseases. The program includes presentations on standard, investigational and experimental therapeutics as well as intensity-modulated radiation therapy, treatment planning, alternative fractionation, and molecular and radiation biology. Specific clinical areas include breast, central nervous system, gastrointestinal, genitourinary, gynecological, head and neck, and lung cancers. In addition, the program addresses quality of life, supportive care and socioeconomic issues. These topics are addressed by a combination of educational sessions, panel discussions, proffered papers and posters. Since a diminishing number of tumors can be managed solely by radiation therapy, among the most noteworthy developments this year were the combined modality approaches (i.e. radiation therapy combined with chemotherapy) in the treatment of malignant disease. In particular, a cluster of seminal papers was presented pertaining to colorectal and pulmonary (both small cell and non-small cell lung cancer) malignancies. This report focuses on the advances reported for those tumor types, which are among the most prevalent in the Western world.

Clinical Trials, Phase II as Topic↗

PubMed1993

Treatment of community-acquired pneumonia. A multicenter, double-blind, randomized study comparing clarithromycin with erythromycin. Canada-Sweden Clarithromycin-Pneumonia Study Group.

The efficacy and safety of orally administered clarithromycin and erythromycin in the treatment of community-acquired pneumonia were assessed in a multicenter, double-blind, randomized study. Two hundred sixty-eight patients were randomized to receive either clarithromycin, 250 mg twice a day, or erythromycin stearate, 500 mg 4 times a day, for 7 to 14 days. Efficacy was evaluable in 173 patients (92 for clarithromycin, 81 for erythromycin). No statistically significant difference in clinical success rate (cure or improvement) was observed between the two groups (clarithromycin, 97 percent; erythromycin, 96 percent). Both groups had identical radiologic response (97 percent with resolution or improvement). Similarly, no statistically significant difference in bacteriologic response toward the target pathogens was observed among evaluable patients (clarithromycin, 23/26; erythromycin, 17/17; p value = 0.287). Clinical response toward Mycoplasma and Chlamydia pneumonia was comparable between the two groups (clarithromycin, 15/16; erythromycin, 10/11). However, patients receiving erythromycin had a twofold higher incidence of adverse events, mostly related to the gastrointestinal system, and were five times more likely to withdraw from therapy because of drug-related adverse events. These results show that clarithromycin is as effective as erythromycin in the outpatient treatment of community-acquired pneumonia. Furthermore, the lower incidence of adverse events associated with clarithromycin indicates that it is more acceptable to patients and, therefore, can enhance compliance.

Adolescent↗

PubMed1995

Bariatric Surgery Postoperative Behavioral Change: The Importance of Ongoing Assessment and Teaching.

In bariatric surgery we modify, in varying degrees, the gastrointestinal system. We observe the patients clinically over the postoperative period of a few months or more. During this time our main concern is to monitor them physiologically, noting the decline in weight, change in body structure, and vast improvement in their comorbidities. Frequently the reaction of the patient may be somewhat surprising to us. One or 2 years past surgery they have forgotten about having had diabetes and hypertension, diseases for which they had received a barrage of medical treatment. It does not seem to matter anymore that at one time they wore a size 2X and now can wear size 14. Now we are forced to wonder what the expectation of the patient was. Our goal was to improve their physiological and psychological well-being, assuming they would go hand in hand with weight loss. If the patient does not recognize an improvement in their quality of life and continues to question their self-worth, then perhaps we should reassess our goals and our obligations. The principles of surgery and how it is or should be done is fairly clear. If we are to maintain standards of quality in this particular field of medicine, we must recognize our commitment to patients and make these principles just as clear. The commitment involves ongoing postoperative assessment and teaching, assessment of emotional well-being and lessons in dietary and physical activity, including exposure to and involvement in group support.

Journal Article↗

PubMed2004

The change of asthma course during pregnancy.

The course of asthma during pregnancy is variable. When the total pregnant asthmatic population is considered, one-third improve, one-third are unchanged, and one-third experience increased symptoms. The course of asthma may be influenced by the many physiologic changes during pregnancy as well as the severity of the pre-existing asthma. Prospective studies have found that severe asthmatics have exacerbations during pregnancy more often than mild asthmatics. The first trimester and the last month of pregnancy are relatively free of exacerbations. The second and third trimesters have more potential for increased asthma symptoms and the need for medications. Change in allergic nasal symptoms may precede similar changes in asthma during pregnancy. The course of asthma during labor and delivery is worsened in only 10% of patients, and their problems are usually mild. Postpartum most women return to their prepregnant state within 3 mo. Physiologic changes in pregnancy affect the pulmonary function with a decrease in functional residual capacity (FRC) and 50% increase in minute ventilation. This change results in hyperventilation in 60-70% of normal pregnancies and a sensation of dyspnea that can be distressing to an asthmatic. There is also nasal congestion in 22-72% of pregnancies beginning in the second trimester, which can also affect asthma. The gastrointestinal system is affected in pregnancy with one-third of women having gastroesophageal reflex disease (GERD). Undertreatment of asthma during pregnancy remains a problem in emergency departments. With awareness of the patient's prepregnant state, careful monitoring during pregnancy will prevent serious exacerbations and complications.

Asthma↗

PubMed2005

A case of hemangiosarcoma in thyroid with severe anemia due to bone marrow metastasis.

A 56-year-old woman presented with rapidly enlarging thyroid mass and deep anemia. There was no history of gastrointestinal bleeding, and endoscopic examinations of the gastrointestinal system were normal. Fine needle aspiration cytology from the thyroid nodule was suspicious. After blood transfusion, total thyroidectomy was performed. Postoperative histopathological examination of the specimen revealed hemangiosarcoma of the thyroid. After establishment of the diagnosis chemotherapy was started. But hemoglobin values decreased again and hepatosplenomegaly developed at the second month of surgery. Bone marrow aspiration cytology which was performed demonstrated the same tumoral cells infiltrating bone marrow. The patient died at 12th week after surgery. Thyroid hemangiosarcoma can metastasize to the bone marrow and anemia may be an indicator of the advanced disease. In the differential diagnosis of the anemia, bone marrow metastasis and bone marrow biopsy should be considered in suspected cases.

Anemia↗

PubMedDate not supplied

Congenital hypothyroidism and concomitant anomalies.

To search for concomitant anomalies among babies with congenital hypothyroidism, 120 newborn babies with confirmed congenital hypothyroidism were studied at the Veterans General Hospital, Taipei. The incidence of concomitant anomalies was estimated to be 11.67% (14/120). Among these anomalies, cardiac and gastrointestinal systems were the most commonly involved, comprising 35.7% (5/14) and 28.6% (4/14) of all anomalies, respectively. The type (i.e. agenesis, ectopia or eutopic goiter) as well as the severity of hypothyroidism were analyzed between groups of babies with or without concomitant anomalies. No differences existed between the two groups of babies regarding these two aspects.

Congenital Abnormalities↗

PubMed2006

Retrospective diagnosis of hypoxic myocardial injury in premature newborns.

UNLABELLED: Perinatal asphyxia has a high impact on neonatal mortality, morbidity, and neurological outcome. The hypoxic effects on brain, kidney and gastrointestinal system are well recognized in newborns. While it is known that hypoxia also effects cardiac function, there are few studies of quantitative myocardial injury in premature infants who suffered hypoxia. AIM: To investigate usefulness of cardiac troponin (cTnT) and creatinine kinase MB (CK-MB) in the diagnosis of myocardial injury due to birth hypoxia and to correlate these markers with cardiac functions as measured by echocardiogram. METHODS: We studied 43 preterm infants: 21 with birth asphyxia and 22 controls. Echocardiographic studies and quantitative determination of cTnT and CK-MB in blood serum was performed between the 12(th) and the 24(th) h of life. RESULTS: cTnT and CK-MB levels were higher in asphyxiated infants compared to controls (0.287 +/- 0.190 vs. 0.112 +/- 0.099 ng/mL, P < 0.001) and (18.35 +/-14.81 vs. 11.09 +/- 5.17 ng/L, P < 0.05). Among controls, we observed an elevated value of cTnT in those with respiratory distress syndrome (RDS). We found a decrease in fractional shortening (P < 0.05) and an increase in tricuspid insufficiency (P < 0.01) in asphyxiated newborns. CONCLUSIONS: cTnT and CK-MB levels are strong indicators of myocardial injury due to perinatal hypoxia. The cTnT level was most strongly related to RDS.

Asphyxia Neonatorum↗

PubMed2001

Current status and new developments with galantamine in the treatment of Alzheimer's disease.

Galantamine is a newly available cholinergic drug that offsets reductions in central cholinergic neurotransmission in Alzheimer's disease (AD) by specifically and reversibly inhibiting acetylcholinesterase (AChE) and by allosterically modulating nicotinic cholinergic receptors. The clinical impact of this latter mechanism of action has not been fully elucidated. Galantamine has favourable pharmacokinetic features including linear elimination kinetics, a relatively short half-life and high oral bioavailability. The efficacy of galantamine has been studied in an extensive clinical development program. During randomised, double-blind, placebo-controlled trials of up to 6 months' duration, galantamine 16 and 24 mg/day consistently produced a broad spectrum of beneficial effects on cognitive and non-cognitive AD symptoms. Patients' cognition, global function and abilities to perform both instrumental and basic activities of daily living were maintained, the emergence of behavioural symptoms was postponed and apparent reductions in caregiver burden were seen. In long-term studies (> or = 12 months), galantamine maintained cognitive and functional abilities at or near baseline levels for at least 12 months. Again, these benefits were associated with decreases in caregiver burden. The incidence of adverse events, which are typically mild or moderate in severity, is generally low with galantamine. Cholinergically mediated adverse events affecting mainly the gastrointestinal system can be minimised using the recommended slow dose-escalation regimen. Galantamine may therefore help reduce the overall burden and cost involved in caring for AD patients. Being approved for the treatment of mild-to-moderately severe AD in both the US and in Europe, with trials of its efficacy in other dementia types already yielding positive results, galantamine ranks as a first-line therapy for dementia.

Aged↗

PubMed2001

Review of rivastigmine and its clinical applications in Alzheimer's disease and related disorders.

Rivastigmine (Exelontrade mark, Novartis) is a novel intermediate-acting reversible and non-competitive carbamate acetylcholinesterase (AChE) that was recently introduced for the treatment of Alzheimer's disease (AD). Preclinical studies have shown that rivastigmine has many similarities to other currently available cholinesterase inhibitors (ChEIs) and some important differences. The drug has been evaluated for this use in two well designed, published, adequately powered, Phase III, 26 week clinical trials that included a total of more than 1500 rivastigmine and 700 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. These studies indicate that rivastigmine (6 - 12 mg/day) usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild-to-moderate AD, with higher doses producing more benefits. Rivastigmine is beneficial in all three domains (namely cognition, daily activities and behaviour) of AD. Data on long-term efficacy support continued benefits of rivastigmine beyond 6 months. Rivastigmine is generally well-tolerated with no requirement for routine electrocardiogram (ECG) or blood monitoring. Rivastigmine causes adverse events that are generally those expected from a ChEI and mainly involve gastrointestinal system. They are usually mild-to-moderate, of short duration and responsive to dosage reduction. They occur mostly during the dosage titration phase and decrease during the maintenance phase. Clinically significant drug-drug interactions are unlikely. The consistent efficacy in treating all three domains (cognition, daily functioning and behaviour) and good tolerability, particularly with slow titration, makes rivastigmine a good first-line ChEI therapy for the treatment of AD. Therapeutic dose range is 6 - 12 mg/day. Rivastigmine should be started at 1.5 mg b.i.d. with meals and increased at 2 - 4 week intervals to achieve the highest tolerated dose.

Alzheimer Disease↗