Design of a Novel Online, Modular, Flipped-classroom Surgical Curriculum for East, Central, and Southern Africa.

Objective: We describe a structured approach to developing a standardized curriculum for surgical trainees in East, Central, and Southern Africa (ECSA). Summary Background Data: Surgical education is essential to closing the surgical access gap in ECSA. Given its importance for surgical education, the development of a standardized curriculum was deemed necessary. Methods: We utilized Kern's 6-step approach to curriculum development to design an online, modular, flipped-classroom surgical curriculum. Steps included global and targeted needs assessments, determination of goals and objectives, the establishment of educational strategies, implementation, and evaluation. Results: Global needs assessment identified the development of a standardized curriculum as an essential next step in the growth of surgical education programs in ECSA. Targeted needs assessment of stakeholders found medical knowledge challenges, regulatory requirements, language variance, content gaps, expense and availability of resources, faculty numbers, and content delivery method to be factors to inform curriculum design. Goals emerged to increase uniformity and consistency in training, create contextually relevant material, incorporate best educational practices, reduce faculty burden, and ease content delivery and updates. Educational strategies centered on developing an online, flipped-classroom, modular curriculum emphasizing textual simplicity, multimedia components, and incorporation of active learning strategies. The implementation process involved establishing thematic topics and subtopics, the content of which was authored by regional surgeon educators and edited by content experts. Evaluation was performed by recording participation, soliciting user feedback, and evaluating scores on a certification examination. Conclusions: We present the systematic design of a large-scale, context-relevant, data-driven surgical curriculum for the ECSA region.

Correlation between the structure and function of the rabbit urinary bladder following partial outlet obstruction.

PURPOSE: To understand the relationship between contractile and structural changes in the obstructed bladder, rabbit bladder was partially obstructed for up to 70 days and alterations in tension response to field stimulation and carbachol were compared with alterations in ultrastructure and innervation of detrusor smooth muscle (SM). The effect of partial outlet obstruction on the physiological responses to field stimulation (FS) (nerve mediated contraction) and carbachol (receptor mediated contraction) were correlated with the structure and innervation of the detrusor smooth muscle (SM) of the same animal during a 70 day period. MATERIALS AND METHODS: 28 rabbits were subjected to 1 to 70 days of mild partial outlet obstruction. Sham operated rabbits were euthanized at 7, 14, 28, and 70 days post-obstruction. At each time period, isolated strips of bladder body were mounted in individual baths and the contractile response to FS and carbachol determined. Three additional strips from each bladder were fixed for electron microscopy. RESULTS: Bladder mass increased rapidly during the first 7 days after obstruction, was constant for the next 7 days, and then continued to increase gradually. Dysfunction of the contractile response to FS was noted as early as 3 days and progressively increased over the 70-day study period. The decrease in the response to FS increased at a significantly faster rate than the decrease in the contractile response to carbachol. In ultrastructure studies, at 3 and 7 days post-obstruction the majority of SM cells displayed the characteristics of hypertrophy. At 28 days some SM cells displayed loosely packed myofilaments and an irregular distribution of sarcoplasmic dense bodies. At 70 days swollen mitochondria were present in all cell types of the bladder wall. Evidence of axonal degeneration was first observed at 7 days post-obstruction and became more extensive thereafter. No evidence of mitotic figures, nerve growth cones or regenerating SM cells was observed. CONCLUSIONS: Prolonged partial bladder outflow obstruction is accompanied by a progressive decrease in contractility of SM. The present study describes the structural damage that occurs in the bladder wall in response to partial outlet obstruction and correlates these observations with the contractile dysfunction with which it is associated. Furthermore, mitochondrial damage in vessels and fibroblasts is suggestive of bladder wall ischemia.

The distribution of vesicular acetylcholine transporter in the human male genitourinary organs and its co-localization with neuropeptide Y and nitric oxide synthase.

Because doubt still remains concerning the distribution of nerves that are unequivocally cholinergic in the human genitourinary organs, we have used a specific marker, namely, an antibody to vesicular acetylcholine transporter (VAChT), to immunolabel cholinergic axons and cell bodies in specimens of urinary bladder, seminal vesicle, vas deferens, and prostate gland obtained from neonates and children post mortem. In addition some sections were double-immunolabeled with VAChT and either neuropeptide Y (NPY) or nitric oxide synthase (NOS). The results demonstrated a rich cholinergic innervation to the muscle coat of the bladder body with a much less prominent, but nonetheless significant, cholinergic innervation to the smooth muscle components of the seminal vesicle, vas deferens, and prostate. Small ganglia were scattered throughout the detrusor muscle of the urinary bladder, approximately 75% of the intramural neurons being VAChT immunoreactive, whereas approximately 95% contained NPY and approximately 40% contained NOS. VAChT immunoreactivity was observed in 40% of neurons in ganglia scattered throughout the pelvic plexus. Almost all these cholinergic neurons contained NPY and approximately 65% contained NOS. Almost all the cholinergic nerve fibers throughout the genitourinary organs also contained NPY. Although NOS was sparse in the cholinergic nerves of the bladder body, it occurred in the majority of cholinergic nerves at the bladder neck and was also present in a proportion of the cholinergic nerves in the other organs examined. VAChT-immunoreactive nerves were also observed in a sub-epithelial location in all the organs examined, the majority containing NPY, whereas a small proportion contained NOS. Although doubt remains about the function of sub-epithelial cholinergic nerves in the urinary bladder, the majority of similar nerves in the seminal vesicle, vas deferens, and prostate gland are considered to be secretomotor. Collectively these findings demonstrate that the cholinergic innervation of the male genitourinary system is well established in the neonate and child. Neurourol. Urodynam. 19:185-194, 2000.

Lamivudine for the treatment of chronic hepatitis B.

Lamivudine (Zeffix) is the first of a new class of antiviral agents to become available for the treatment of chronic hepatitis B. The results of controlled clinical trials indicate that in most patients, lamivudine improves necro-inflammatory liver disease, reduces the progression of hepatic fibrosis, normalises serum alanine aminotransferase, and enhances hepatitis B e antigen (HBeAg) seroconversion. For patients with HBeAg-positive chronic hepatitis B, one year of lamivudine therapy results in HBeAg seroconversion rates similar to those obtained with a standard course of interferon-alpha. Moreover, results from two and three years of lamivudine therapy show that the cumulative HBeAg seroconversion rate continues to increase with extended lamivudine therapy. Even in the absence of HBeAg seroconversion, lamivudine therapy leads to improvements in liver disease in many patients. HBV strains (YMDD variants) with reduced in vitro sensitivity to lamivudine were detected in some patients after at least 9 months therapy. Although the clinical benefits to lamivudine were greatest for those patients who remained free of YMDD variants, one year of lamivudine therapy led to improvements in most response parameters compared with placebo, regardless of whether YMDD variants were detected. Controlled and open-label studies show that lamivudine may provide similar benefits to other important groups of patients with chronic hepatitis B, including those with pre-core mutant disease and those with hepatic decompensation. Lamivudine was well tolerated in all patient groups studied. The incidence of adverse events was consistently similar in patients who received lamivudine compared with those given placebo. In conclusion, extensive clinical data provide evidence that lamivudine is a well-tolerated, effective, and convenient medicine for patients with chronic hepatitis B.

The distribution of noradrenergic nerves in the human lower urinary tract. A review.

The purpose of this presentation is to describe the distribution of noradrenergic nerves in the human genitourinary system. The techniques which have been employed include formaldehyde-induced fluorescence and immunocytochemical methods to demonstrate dopamine beta-hydroxylase and tyrosine hydroxylase. These methods have been applied to human fetal, neonatal, infant, child and adult tissues removed either at post mortem examination or by surgical excision. The innervation of the fetal urinary bladder is well established by 13 weeks and, as in older specimens, the detrusor receives a sparse noradrenergic nerve supply. In contrast the smooth muscle of the terminal ureter is well supplied by this type of autonomic nerve. An additional incomplete muscle layer has been identified as a nomal component of the terminal ureter which is richly innervated by noradrenergic nerves. In some cases this muscle forms a complete collar which may be responsible for ureteric obstruction. By comparison with the detrusor, bladder neck smooth muscle receives a dense noradrenergic nerve supply particularly in the male. Unlike the detrusor, the structure and innervation of the vas deferens, seminal vesicle and prostate are poorly differentiated in the fetus. In the infant and child, the structure of the intramural smooth muscle of these organs remains immature although a rich noradrenergic nerve supply resembing the adult has been established in the fetus by 30 weeks. In the fetus, autonomic ganglia occur in association with noradrenaline rich paraganglia and surprisingly, with sensory nerve endings resembling pacinian corpuscles. Shortly after birth paraganglia are no longer associated with the autonomic ganglia of the genitourinary system. On the basis of size at least two types of autonomic neuron populate these autonomic ganglia. One type is relatively large and devoid of catecholamines but is closely associated with pericellular noradrenergic nerve fibres. The second type of neuron is small, contains noradrenaline and is arranged in clusters closely related to the capsule of the prostate gland. The significance of these observations will be considered with respect to the neurological control of the genitourinary system.

Tyrosine hydroxylase and vesicular acetylcholine transporter are coexpressed in a high proportion of intramural neurons of the human neonatal and child urinary bladder.

Autonomic ganglia of the human pelvic plexus contain sympathetic and parasympathetic neurons which innervate the internal reproductive organs and the lower urinary tract while the urinary bladder also receives innervation from small intramural ganglia embedded in the detrusor muscle. Previous studies have used the immunocytochemical demonstration of tyrosine hydroxylase (TH), either alone or in combination with dopamine beta-hydroxylase, to identify noradrenergic neurons in these ganglia. However until recently a reliable marker for cholinergic neurons in the human autonomic nervous system was not available since antibodies to choline acetyltransferase do not react in this tissue. The present immunohistochemical study has used an antibody to human vesicular acetylcholine transporter (VAChT) to identify cholinergic neurons in the pelvic plexus and intramural bladder ganglia in a series of specimens from human male neonates and children. Immunostaining for TH was also carried out on the same sections and the results showed that while the vast majority of pelvic ganglion neurons were either cholinergic or noradrenergic (as seen by the presence of VAChT or TH respectively), approximately 50% of the neurons in the intramural ganglia were labeled with both immunomarkers. The presence of TH in cholinergic neurons may be due to the immaturity of the tissues examined since previous data on intramural bladder ganglia in the adult have shown that a much smaller proportion of the neurons contain TH than was observed in the present study. It is concluded that the presence of TH alone cannot be regarded as a specific marker for noradrenergic neurons in the genitourinary system of the human neonate and child.

Colocalisation of neuropeptides, nitric oxide synthase and immunomarkers for catecholamines in nerve fibres of the adult human vas deferens.

Single and double-label immunofluorescence methods were used to determine the distribution and patterns of colocalisation of various neuropeptides and nitric oxide synthase (NOS) with the catecholamine synthesising enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DbetaH) in nerve fibres within specimens of adult human vas deferens obtained at vasectomy (age range 28 to 83 y). Cholinergic nerve fibres were immunolabelled with an antiserum to vesicular acetylcholine transporter (VAChT). Using the general nerve marker protein gene product 9.5 (PGP) the density of intramural nerve fibres was found to be similar irrespective of age. Many of these axons, especially in the outer 2 muscle layers were TH and DbetaH-immunoreactive (IR) and were thus confirmed as noradrenergic. Fewer such axons were seen in the inner longitudinal muscle layer. All the noradrenergic nerve fibres also displayed NPY-immunoreactivity with minor populations containing galanin (GAL) or somatostatin (SOM). Nerve fibres lacking TH and DbetaH-IR were immunoreactive for VAChT and were sparsely distributed throughout the 2 outer muscle layers but more numerous in the inner muscle layer. Nerves lacking TH and DbetaH were immunoreactive for NPY and some also contained NOS, VIP or CGRP. These results have been compared with those obtained previously from specimens of human neonatal and infant vas deferens where, in contrast to the present results, NOS and VIP were shown to be colocalised with TH in many of the intramuscular nerve fibres. It thus appears that NOS and VIP cease their coexistence with TH in intramuscular nerve fibres of the human vas deferens between the pre- and postpubertal states. In addition to the intramuscular nerve fibres a VAChT-IR subepithelial nerve plexus occurs in the vas deferens and may control the secretory activity of the lining epithelium. Most of these subepithelial nerve fibres were immunoreactive for NPY and many also contained VIP while minor populations were immunoreactive for NOS, GAL, SOM or SP although fibres containing CGRP were not observed. The neuropeptide content of the subepithelial nerve plexus was similar to that observed in the infant, except for an increased density of VIP-IR nerves, which may reflect greater activity of the lining epithelial cells in the adult vas deferens.

Feature trees: a new molecular similarity measure based on tree matching.

In this paper we present a new method for evaluating molecular similarity between small organic compounds. Instead of a linear representation like fingerprints, a more complex description, a feature tree, is calculated for a molecule. A feature tree represents hydrophobic fragments and functional groups of the molecule and the way these groups are linked together. Each node in the tree is labeled with a set of features representing chemical properties of the part of the molecule corresponding to the node. The comparison of feature trees is based on matching subtrees of two feature trees onto each other. Two algorithms for tackling the matching problem are described throughout this paper. On a dataset of about 1000 molecules, we demonstrate the ability of our approach to identify molecules belonging to the same class of inhibitors. With a second dataset of 58 molecules with known binding modes taken from the Brookhaven Protein Data Bank, we show that the matchings produced by our algorithms are compatible with the relative orientation of the molecules in the active site in 61% of the test cases. The average computation time for a pair comparison is about 50 ms on a current workstation.

Structure and autonomic innervation of the human vas deferens: a review.

The motor innervation of the smooth muscle coat of the human vas deferens is predominantly noradrenergic in type while a less dense and differently distributed presumptive cholinergic innervation is also in evidence, although the precise role of the latter is undetermined. Immunohistochemical studies have confirmed the presence of catecholamine-synthesizing enzymes tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) in the majority of fine, varicose intramuscular nerves, about two-thirds of which also contain neuropeptide Y (NPY). Minor populations of noradrenergic nerves contain enkephalin (ENK), galanin (GAL), somatostatin (SOM), or nitric oxide synthase (NOS). The presumptive cholinergic intramuscular nerves contain vasoactive intestinal polypeptide (VIP) and NPY. The subepithelial nerves of the vas deferens are assumed to have a secretomotor function and are rich in acetylcholinesterase and NPY, many also containing either VIP or NOS. The muscle coat of the human vas deferens is poorly differentiated until after birth, the intramuscular nerves in the fetus being relatively thick and non-varicose. Development of a subepithelial nerve plexus lags behind that in the muscle coat but its density in the neonatal vas deferens resembles that seen in the adult. Observations on specimens of human vas deferens obtained at vasovasostomy carried out 1 to 15 years after vasectomy have shown a marked reduction in the density of noradrenergic nerves in the muscle coat of the testicular portion while that in the urethral portion remains unaltered. Furthermore, the subepithelial secretomotor nerves degenerate in the testicular portion. These long-term changes in the pattern of innervation of the vas deferens consequent upon vasectomy may have profound effects upon the outcome of vasovasostomy with respect to subsequent sperm maturation, transport, and viability.

Immunohistochemical characteristics of human paraganglion cells and sensory corpuscles associated with the urinary bladder. A developmental study in the male fetus, neonate and infant.

Triple label immunohistochemistry was used to study the coexistence of the catecholamine-synthesising enzymes dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) and several neuropeptides including neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SOM) and galanin (GAL) as well as nitric oxide synthase (NOS) in developing pelvic paraganglion cells in a series of human male fetal, neonatal and infant specimens ranging in age from 13 wk of gestation to 3 y postnatal. 13-20 wk old fetal specimens possessed large clusters of paraganglion cells lying lateral to the urinary bladder and prostate gland which were intensely DBH-immunoreactive (-IR) but lacked TH, NOS and the neuropeptides investigated. With increasing fetal age small clusters of paraganglion cells were observed in the muscle coat of the urinary bladder. At 23 wk of gestation occasional paraganglion cells were NOS or NPY-IR while at 26 wk of gestation the majority of paraganglion cells were TH-IR and a few were SOM or GAL-IR. Some postnatal paraganglia within the bladder musculature contained cells which were all VIP, SP or CGRP-IR while others displayed coexistence of NOS and NPY, SP and CGRP, or NPY and VIP. The presence of NOS in certain paraganglion cells indicates their capacity to generate nitric oxide (NO). These results show that human paraganglion cells develop different phenotypes possibly dependent upon their location within the bladder wall. A delicate plexus of branching varicose nerves was observed in the fetal paraganglia which increased in density with increasing gestational age. The majority of these nerves were VIP-IR while others were CGRP, SP, NPY, NOS or GAL-IR. The presence of nerve terminals adjacent to the paraganglion cells implies a neural influence on the functional activity of the paraganglia. Some paraganglia in the late fetal and early postnatal specimens contained Timofeew's sensory corpuscles, resembling pacinian corpuscles in their morphology. The central nerve fibre of these corpuscles displayed immunoreactivity for SP, CGRP and NOS, the latter indicating a possible role for NO in afferent transmission from the urinary bladder. In addition, a few corpuscles were penetrated by a noradrenergic nerve fibre immunoreactive for NPY and TH, which may have a modulatory role on the sensory receptor.

The vesico-ureteric junction in three cases of primary obstructive megaureter associated with ectopic ureteric insertion.

OBJECTIVE: To examine the histological structure and autonomic innervation of the vesico-ureteric junction (VUJ) in three cases of primary obstructive megaureter occurring in association with ectopic ureteric insertion. PATIENTS AND METHODS: Specimens of VUJ were obtained from one male and two females with primary obstructive megaureter and ectopic ureteric insertions. Serial frozen sections were cut and stained with either Masson's trichrome or immunostained for protein gene product (PGP 9.5; a general nerve marker) or dopamine beta-hydroxylase (DbetaH), a marker for noradrenergic nerves. RESULTS: In each case examined the terminal ureter was encircled by a thick collar of smooth muscle on the inside of which lay normal narrow-diameter longitudinally orientated ureteric muscle bundles. Loose connective tissue separated the surrounding detrusor muscle from this abnormal muscle collar, which was formed of distinctive smooth muscle cells arranged in a meshwork. The autonomic innervation of the ureteric and detrusor muscle bundles was similar to that previously reported for the normal VUJ while the thick muscle collar was richly innervated by DbetaH-immunoreactive noradrenergic nerves. CONCLUSION: The presence of an additional smooth muscle collar surrounding the terminal ureter may impede the normal flow of urine from ureter to bladder and be the cause of megaureter in these patients. We propose that the presence of this muscular collar arises from the developmental anomaly and suggest that these cases represent a subgroup that requires early surgical treatment.

The structure and autonomic innervation of the vesico-ureteric junction in cases of primary ureteric reflux.

OBJECTIVE: To determine the histological structure and autonomic innervation of the vesico-ureteric junction (VUJ) in cases of primary ureteric reflux, to compare the results with those reported previously for non-refluxing VUJs and thus determine possible structural anomalies which could be responsible for vesico-ureteric reflux (VUR). MATERIALS AND METHODS: Nineteen specimens of VUJs with reflux were obtained from four males and 10 females undergoing ureteric reimplantation. Serial frozen sections were cut and stained either with Masson's trichrome or immunostained for protein gene product (PGP 9.5), a general nerve marker, dopamine beta hydroxylase (D beta H), a marker for noradrenergic nerves, or neuropeptide Y (NPY). RESULTS: Longitudinally orientated muscle bundles of narrow diameter accompanied the ureter to its termination at the ureteric orifice. Where they merged with those of the superficial trigone. In some specimens, an additional muscle component was identified, situated on the outer aspect of the ureteric muscle coat, consisting of an incomplete layer of distinctive muscle whose constituent cells formed an interlacing mesh-work. Occasionally, specimens included detrusor muscle which consisted of relatively large diameter compact bundles separated from the ureter by a connective tissue sheath. D beta H- and NPY-immunoreactive (-IR) nerves were numerous among the ureteric muscle bundles. Many NPY-IR nerves occurred within the detrusor muscle while D beta H-IR nerves were mainly perivascular. When present, the outer muscle component was richly innervated by both D beta H- and NPY-IR nerves. PGP immunoreactivity varied among regions in the same section, PGP-IR nerves frequently being less numerous than those containing D beta H or NPY. CONCLUSION: These results indicate that the morphology of the VUJ in cases of VUR is indistinguishable from the normal VUJ described previously. Furthermore, the density and distribution of D beta H- and NPY-IR nerves is identical to that in controls. However, the antigenicity of PGP in the reflux specimens appears to be masked in some regions by an unknown factor.

Co-localization of nitric oxide synthase, neuropeptides and tyrosine hydroxylase in nerves supplying the human post-natal vas deferens and seminal vesicle.

OBJECTIVE: To determine the distribution and patterns of co-localization of nitric oxide synthase (NOS), neuropeptides and tyrosine hydroxylase (TH) in intrinsic nerves of the human post-natal vas deferens and seminal vesicle. MATERIALS AND METHODS: Double and triple immunolabelling methods were used in tissue from 10 male infants and children (age range 2 months to 3 years) obtained at post-mortem examinations carried out within 12 h of death. RESULTS: Most nerves supplying the muscle coat of either organ were TH-immunoreactive (-IR), most of which also contained neuropeptide Y (NPY) while a smaller proportion contained both NPY and NOS. Minor populations of the TH/NPY-IR intramuscular nerves contained calcitonin gene-related peptide (CGRP), galanin (GAL), met-enkephalin (m-ENK) or vasoactive intestinal polypeptide (VIP). Non-TH-IR intramuscular nerves were relatively infrequent and most contained NPY and either VIP or NOS. Presumptive secretomotor nerves formed subepithelial plexuses in both organs, most of which contained NPY co-localized with either VIP or NOS, with minor populations containing CGRP and/or GAL. TH- and substance P (SP) -IR nerves were not observed subepithelially. Perivascular nerve plexuses were mainly formed by TH-IR varicose nerves, most of which contained co-localized NPY and CGRP, with a smaller proportion containing NPY and NOS and minor populations containing VIP, m-ENK, SP or GAL. CONCLUSION: These results indicate that the autonomic control of the human vas deferens and seminal vesicle is provided by several immunohistochemically distinct nerve populations. Furthermore, NOS is present in a proportion of both the noradrenergic and non-noradrenergic nerves. Pharmacological studies are now required to elucidate the precise roles of nitric oxide and neuropeptides in the functional control of these organs.

A double-label immunohistochemical study of intramural ganglia from the human male urinary bladder neck.

Double-label immunocytochemistry was used to investigate the colocalisation of various neuropeptides and the enzymes nitric oxide synthase (NOS) and tyrosine hydroxylase (TH) in intramural ganglia of the human male urinary bladder neck and trigone. Postmortem specimens were obtained from 7 male infants and children ranging in age from 2 mo to 3 y who had died as a result of cot death or accidental trauma. On average 60% of the intramural neurons were non-TH-immunoreactive (-IR) (i.e. presumptive cholinergic) and 40% were TH- and D beta H-IR (i.e. noradrenergic). Within the non-TH-IR population, calcitonin gene-related peptide (CGRP) was found in 65% of cells, neuropeptide Y (NPY) in 90%, nitric oxide synthase (NOS) in 45%, somatostatin (SOM) in 90%, and vasoactive intestinal polypeptide (VIP) in 40%. The corresponding values for the TH-IR neurons were CGRP (54%), NPY (70%), NOS (58%), SOM (73%) and VIP (40%). All the observed bombesin (BOM)-immunoreactivity was colocalised with TH while 90% of VIP and almost all the CGRP was colocalised with NPY. Less than 5% of neurons were immunoreactive for substance P (SP) or met-enkephalin (m-ENK) and some of these also contained TH. Varicose nerve fibres were seen in close proximity to some of the intramural neurons, the majority of such varicosities showing immunoreactivity to CGRP, VIP or TH. Less common were pericellular varicosities immunoreactive to NPY, SOM or SP. These results demonstrate the neurochemical heterogeneity of intramural neurons in the human bladder neck and provide indirect evidence for the complexity of the peripheral innervation of the human urinary bladder.

Evaluation of the CASP2 docking section.

The docking section of CASP2 is reviewed. Seven small molecule ligand-protein targets and one protein-protein target were available for predictions. Many of the small molecule ligand complexes involved serine proteases. Overall results for the small molecule targets were good, with at least one prediction for each target being within 3 A root-mean-square deviation (RMSD) for nearly all targets and within 2 A RMSD for over half the targets. However, no single docking method seemed to consistently perform best. In addition, the predictions closest to the experimental results were not always those ranked the highest, pointing out that the evaluation (scoring) of potential solutions is still an area that needs improvement. The protein-protein target proved more difficult. None of the predictions did well in reproducing the geometry of the complex, although in many cases the interacting surfaces of the two proteins were predicted with reasonable accuracy. This target consisted of two large proteins and, therefore was a demanding target for docking methods.

Clarithromycin dual therapy regimens for eradication of Helicobacter pylori: a review.

BACKGROUND: Peptic ulcer disease can be cured by eradication of Helicobacter pylori during treatment to heal the ulcer. Dual therapy regimens were among the first to be granted approval for use. Reports of dual therapies including clarithromycin as the sole antibiotic are reviewed. METHODS: Reports were identified from literature up to May 1997. Information reviewed included patient population, medical diagnosis, trial design, eradication regimens, and H. pylori eradication rates. The great diversity between studies limits formal meta-analysis but a measure of relative efficacy has been obtained by comparison of eradication rates derived by clearly defined methods and by pooling data. RESULTS: Seventy-five reports of trials with 104 dual therapy treatment arms were reviewed. H. pylori eradication rates reported with ranitidine bismuth citrate plus clarithromycin range from 70-96% with a pooled observed rate of 85%. With omeprazole plus clarithromycin, reported eradication rates range from 27-90% with the pooled reported rate being 66%. Few data are available with either lansoprazole or ranitidine hydrochloride plus clarithromycin. CONCLUSION: High H. pylori eradication rates derived by consistent and clearly defined methods have been seen with ranitidine bismuth citrate plus clarithromycin. Lower and more variable rates are reported with clarithromycin and either a proton pump inhibitor or a histamine H2-receptor antagonist.

Ranitidine bismuth citrate plus clarithromycin for the eradication of H. pylori.

Reported observed intention-to-treat eradication rates for ranitidine bismuth citrate plus clarithromycin for 14 days range from 70-86% in studies from the USA and 82-96% in multinational studies carried out primarily in Europe. Two double-blind head-to-head comparisons with omeprazole plus clarithromycin or amoxycillin have shown that ranitidine bismuth citrate plus clarithromycin gives considerably higher eradication rates than the omeprazole based regimens. Ongoing studies will define the efficacy of shorter duration dual therapies and provide further data on two antibiotics with ranitidine bismuth citrate. The possibility that ranitidine bismuth citrate may help in the eradication of resistant organisms and even in the prevention of primary resistance requires further work to expand the preliminary in vitro observations. In the meantime, it can be concluded that ranitidine bismuth citrate, when used in conjunction with clarithromycin for 14 days, is an effective therapy for the eradication of H. pylori.

The safety of ranitidine bismuth citrate in controlled clinical studies.

Ranitidine bismuth citrate (Pylorid, Tritec) is a novel drug which heals peptic ulcers and when co-prescribed with either clarithromycin or amoxycillin eradicatesHelicobacter pylori. In controlled clinical studies it was well-tolerated when given alone or when co-prescribed with either antibiotic. Data from 20 clinical studies are reported in this analysis of safety with almost 5000 patients having received ranitidine bismuth citrate (200, 400, or 800 mg twice daily). The incidence of adverse events reported with this new drug, either alone or with an antibiotic, was not different from or lower than in patients given placebo and was independent of the dose of ranitidine bismuth citrate tested. Most commonly reported events (>1% of patients) were upper respiratory tract infection, constipation, diarrhoea, nausea and vomiting, dizziness, and headache, the latter being the only event reported by >2% of patients who received ranitidine bismuth citrate alone. Adverse events considered by the clinical investigator to be adverse reactions occurred with a similar frequency amongst patients given ranitidine bismuth citrate (8%), ranitidine hydrochloride (6%), or placebo (6%). The incidence of adverse reactions was greater when co-prescribed with amoxycillin (11%) or clarithromycin (20%) although it was not different from that noted with the antibiotics alone. Serious adverse events were reported in similar proportions of patients given placebo, ranitidine bismuth citrate alone or with an antibiotic, and ranitidine hydrochloride (range: <1-2%). The safety profile of ranitidine bismuth citrate was thus comparable to that of ranitidine hydrochloride (Zantac), a drug with a well-established record of safety in clinical use.