Fenestration of the vertebrobasilar junction detected with multidetector computed tomography angiography.

The complex embryonic origin of the vertebrobasilar system may result in a wide range of anatomical variations. It has been hypothesized that the formation of fenestrations are likely to occur due to the failure of regression of the bridging arteries that connect the longitudinal neural arteries during embryogenesis. Fenestration of the vertebrobasilar system is a rare anatomical variation that involves a luminal division of the artery, that has a single origin into two separate and parallel channels which are rejoined distally. Fenestrations are important anatomical variants in patients undergoing endovascular and invasive intracranial interventions. Vascular fenestration has been associated with aneurysms, arteriovenous malformations, neuralgia, and vertebrobasilar ischaemia. We report on 3 cases of fenestration at the vertebrobasilar junction in 1 female and 2 male patients, respectively, using multidetector computed tomography angiography. The length of the fenestrated segment of the artery measured 4.41 mm, 3.90 mm, and 5.90 mm, respectively in the patients. Our report is clinically important as the presence of this anatomical variation may influence the management of cervical and intracranial pathologies. Increased awareness of the prevalence of anatomic variations contributes to the advancement of noninvasive imaging capabilities.

Radiological anatomy of the intracranial vertebral artery in a select South African cohort of patients.

The intracranial segment of the vertebral artery (VA) is the unique part of the artery where the two VAs join to form a single vascular channel, viz. the basilar artery. In addition to this typical description, anatomical variations have been described; the presence of anatomical variation has been associated with some pathological processes, neurological complications, and the risk of vascular diseases in the posterior circulatory territory. We evaluated the typical anatomical features and variations of the VA4 component of the VA in a South African population to provide useful data on the prevalence of variation and morphometry of the distal VA. The study is an observational, retrospective chart review of 554 consecutive South African patients (Black, Indian, and Caucasian) who had been examined with multidetector computed tomography angiography (MDCTA) from January 2009 to September 2019. We observed various anatomical variations in the VA4 segment of the VA. We report the incidence of VA hypoplasia, hypoplastic terminal VA, and atresia. Fenestration and duplicate posterior inferior cerebellar artery (PICA) origin were also observed. The left intracranial VA was significantly larger than the right. Our study shows that anatomical variation of the intracranial VA is common in the population studied, with a total prevalence of 36.5%. Understanding the patterns of anatomical variations of the VAs will contribute significantly to the interpretation of ischemic areas and diagnosis of various diseases in the posterior circulatory territory.

An anatomical investigation of the proximal vertebral arteries (V1, V2) in a select South African population.

INTRODUCTION: The most common type of vascular complication during cervical spine surgery is the vertebral artery (VA) injury. The presence of anatomical variation in the artery's morphology has been a significant factor for arterial injury during surgery. Therefore, physicians planning interventions in the craniospinal region need to be aware of the extents of variations. In addition to vascular injury, anatomical variations can predispose to some pathologies in the posterior circulation territory. To provide useful data to interventional radiologists, anatomists, and surgeons, we evaluated the anatomical features of the V1 and V2 segments of the VA in a South African population. MATERIALS AND METHODS: The study is an observational, retrospective chart review of 554 consecutive South African patients (Black, Indian and White) who had undergone computed tomography angiography (CTA) from January 2009 to September 2019. RESULTS: The VA exhibited morphological variation in its course. We report the incidence of variant origin of the left VA, all from the aortic arch. Variation in the level of entry into the transverse foramen ranged between C7 and C3. A left dominant pattern was observed; we also report on hypoplasia of the VA. In addition, we report incidence of VA tortuosity at V1, V2 to be 76.6% and 32.1%, respectively. CONCLUSIONS: The baseline data established in this study regarding the diameter, variant origin, and level of entry into the transverse foramen will assist neurosurgeons and interventional radiologists in interpreting, diagnosing, and planning and executing various vascular procedures and treatment of pathology in the vicinity of the VA.

Community-based education: Experiences of undergraduate dental therapy students at the University of KwaZulu-Natal, South Africa.

BACKGROUND: Community-based education (CBE) is a learning strategy that provides meaningful opportunities for students to apply theory learnt in a larger social and cultural context in various community settings. Although the benefits of CBE to health professional students are well documented, to date, there is little evidence describing dental therapy students' experiences. OBJECTIVES: To describe the experience of CBE by undergraduate dental therapy students in the School of Health Sciences at the University of KwaZulu-Natal. METHODS: This descriptive study, conducted in 2016, gives insight into the experiences of community-based education among dental therapy students using a self-administered questionnaire eliciting qualitative data. Ethical clearance was obtained from the institution. RESULTS: Students reported perceived benefits of improved professional and personal growth, and a deeper understanding of cultural, social and economic influences on oral health care. Some of the perceived challenges included language barrier, limited resources and adapting to new environments. CONCLUSION: The reported experiences of undergraduate dental therapy students involved in community-based clinical training suggest that students gained awareness of the context-specific challenges facing communities and health professionals in different oral health settings.

Strengths and challenges of community-based clinical training as viewed by academics at the University of KwaZulu-Natal, Durban, South Africa

Background. Community-based education (CBE) is seen as a valuable tool in transforming health professions education by aligning clinical training with graduate competencies and needs of the health system. However, academics involved in the implementation have varied views.Objectives. To explore the experiences and views of academics involved in community-based training in the College of Health Sciences at the University of KwaZulu-Natal, Durban, South Africa. Methods. This qualitative study used interviews and focus group discussions consisting of a purposively selected sample of academics. The interviews were audio taped, transcribed and analysed using thematic analysis.Results. Three main themes emerged from the data analysis: the strengths of CBE, challenges experienced in implementation and academics' suggestions concerning challenges. The strengths included benefits to the institution, students, health system and communities. The main challenges experienced were insufficient support from the institution and the Department of Health (DoH). Suggestions were made by academics to overcome these challenges.Conclusion. The study indicates that CBE is perceived as an important pedagogical approach in transforming health professions education, as it can align clinical training with the business plan of the university and the needs of the health system. However, for the successful implementation of CBE, full support from the university and the DoH is required

The Costs of Delivering Human Papillomavirus Vaccination to Grade 4 Learners in KwaZulu-Natal; South Africa

BACKGROUND:The national human papillomavirus (HPV) vaccination roll-out in South Africa provides two doses of Cervarix to all female Grade 4 learners in state schools. This study estimated the costs of vaccinating all learners in KwaZulu-Natal Province (females or males and females) using either the two- or three-dose strategies for both the bivalent and quadrivalent vaccines.OBJECTIVE:To determine costs of the HPV vaccination programme in KwaZulu-Natal.METHODS:Costs were determined adapting World Health Organization vaccination costing guidelines. RESULTS:The 2014 current cost of delivering three doses of Gardasil was ZAR510 per learner. The projected cost of delivering Cervarix to female learners at two or three doses over the period 2014 - 2018; adjusted for inflation; was ZAR172 717 342 and ZAR250 048 426; respectively. Similarly; the cost for Gardasil at these doses was ZAR197 482 200 and ZAR287 194 361; respectively. For male and female learners the cost for Cervarix over this period at two or three doses was ZAR337 101 132 and ZAR540 150 713; respectively. Similarly; the cost for Gardasil at these doses was ZAR426 597 971 and ZAR620 392 784; respectively. Accounting for population variation for females over 5 years; the cost of two doses of Cervarix ranged from ZAR168 888 677 to ZAR 176 545 977 at the lower and upper 95% confidence intervals (CIs); respectively. For three doses the cost ranged from ZAR244 505 544 to ZAR255 591 263 at the lower and upper 95% CIs; respectively. Similarly; the cost for two doses of Gardasil ranged from ZAR193 104 566 to ZAR201 859 798. For three doses the cost ranged from ZAR280 828 057 to ZAR293 560 614. CONCLUSION:This study gives decision makers a basis for structured planning and cost apportionment to ensure effective roll-out of the HPV vaccination programme

Human papillomavirus (HPV) vaccination of adolescents in the South African private health sector: Lessons from the HPV demonstration project in KwaZulu-Natal.

In South Africa (SA), >4,000 women die annually of cervical cancer, a disease caused by the human papillomavirus (HPV). Infections caused by certain genotypes of HPV increase the risk of cervical cancer. HIV-infected women in particular are more likely to have persistent HPV infection, with higher-risk genotypes. In SA, two vaccines (HPV quadrivalent (types 6, 11, 16, and 18) vaccine, recombinant (Gardasil) and HPV bivalent (types 16 and 18) vaccine, recombinant (Cervarix)) are currently registered for the prevention of HPV-related disease. In the past, there have been significant challenges to achieving high coverage and uptake of vaccination­contributory factors include cost and lack of awareness. An HPV demonstration project among schoolgirls in rural KwaZulu-Natal showed that high vaccine uptake is achievable. In 2014, the National Department of Health launched the national HPV vaccination programme among female learners attending public schools. Awareness of HPV vaccination among healthcare providers, education of parents, teachers and learners, and avoidance of missed opportunities for vaccination are vital to the success of the programme. Primary healthcare practitioners may play an important role in cervical cancer prevention by identifying and offering vaccination to girls who miss the opportunity to be vaccinated at school. HPV vaccination should be considered as one arm of a comprehensive programme of cervical cancer prevention and control.

South Africa's nutritional transition: overweight, obesity, underweight and stunting in female primary school learners in rural KwaZulu-Natal, South Africa.

BACKGROUND: Malnutrition substantially impacts the health outcomes of children. Globally, the childhood prevalence of overweight and obesity has increased, while underweight and stunting (though decreasing) continues to pose a major public health challenge. In low- to middle-income countries, a mixed pattern of over- and undernutrition (nutritional transition) can exist in communities. OBJECTIVE: To describe the prevalence of malnutrition among female learners in the Nongoma and Ceza districts in Zululand, KwaZulu-Natal (KZN). METHODS: We performed a secondary analysis of anthropometric data collected during the 2011 HPV Vaccination Demonstration Project. School health teams, comprising trained nurses, measured the height (in cm) and weight (in kg) of 963 female learners in 31 primary schools. Internationally accepted standardised measures were used as cut-offs for defining overweight, obesity, underweight and stunting. RESULTS: We found evidence of both under- and overnutrition. Overall, 9% of female learners were overweight, 3.8% obese, 4% underweight and 9.2% stunted (using WHO/NCHS criteria). The highest levels of stunting were in the 11 - 12-year age groups, of underweight in the 10-year age group, of overweight and obesity in the 9 - 10-year age groups. Moreover, a proportion of underweight (17.4%), overweight (11.1%) and obese (22.9%) learners were also stunted. CONCLUSION: Our study describes the prevalence of overweight and obesity, wasting and stunting of female learners in KZN and suggests the presence of a nutritional transition in these rural communities; however, further studies are needed. Our findings emphasise the need for health promotion and education programs in schools.

High uptake of Gardasil vaccine among 9 - 12-year-old schoolgirls participating in an HPV vaccination demonstration project in KwaZulu-Natal, South Africa.

BACKGROUND: Cervical cancer is linked to infection of the cervix by oncogenic human papillomavirus (HPV) subtypes. The quadrivalent Gardasil vaccine (against HPV types 6, 11, 16, 18), recommended in girls 9 - 12 years of age, has been shown to be safe, immunogenic and efficacious, with minimal or no side-effects. AIM: To demonstrate the capacity of school health teams to carry out vaccinations within a school environment. OBJECTIVES: To assess the uptake of 3 doses of the vaccine, document lessons learnt and provide recommendations for a national rollout of school-based HPV vaccination for learners. METHODS: Female learners (age 9 - 12 years) from 31 primary schools in Nongoma and Ceza districts (KwaZulu-Natal province, South Africa) were identified for inclusion in the vaccination programme. The 3 doses of vaccine were administered by existing school health teams. Education and training sessions were held with all stakeholders: provincial departments of health and education; school health teams; primary healthcare nurses; hospital doctors and nurses; private practitioners; school principals, teachers and governing bodies; parents; and community and traditional leaders. RESULTS: The overall uptake of the vaccine was found to be high: 99.7%, 97.9% and 97.8% for the first, second and third doses respectively (N = 963). No adverse events were attributed to the HPV vaccine. CONCLUSION: This project demonstrated the successful implementation of HPV vaccination among learners (ages 9 - 12 years) using school health teams.

Recommendations for the development of regulatory guidelines for registration of traditional medicines in South Africa.

The regulation and registration of traditional medicines (TM) continues to present challenges to many countries regardless of the fact that an increased number of the population utilises TM for their health care needs. There have been improvements in the legal and policy framework of South Africa based on the WHO guidelines. However, there are currently no guidelines or framework for the registration of TM in South Africa. This article reviews literature and existing guidelines of specific countries and regions and makes recommendations for South African guidelines.

Review of the cardiovascular safety of COXIBs compared to NSAIDS.

There is no doubt that NSAIDs and COXIBS are the mainstay for managing pain and inflammation in arthritis. Overall, at therapeutically equivalent doses, both NSAIDs and COXIBs provide equivalent analgesic and anti-inflammatory efficacy. However, the gastrointestinal risk associated with NSAIDs is considerable. More recently, the cardiovascular risk associated with NSAIDs and COXIBs has become a concern. Most patients, particularly the young, can benefit from NSAIDs without the risk of serious adverse gastrointestinal or cardiovascular events. However, patients with a previous history of serious gastrointestinal complications and the elderly, who could be at risk, do require alternatives. COXIBs have significant benefits over NSAIDs in reducing the incidence of serious gastrointestinal complications (perforations, ulcers and gastric bleeding). Currently two oral COXIBs are available, celecoxib and lumiracoxib, and one parenteral COXIB, parecoxib. Celecoxib has been on the market for longer and has the largest body of evidence. The older NSAIDs, such as meloxicam, with preferential COX-2 inhibition do not have good long-term evidence of reducing the incidence of serious gastrointestinal complications. However, these agents do have evidence of tolerability, ie, reducing the less-serious gastrointestinal effects, mainly dyspepsia. The South African Rheumatoid Arthritis Association's guidelines, amended in November 2005 recommend COXIBs for elderly patients (> 60 years) with previous gastropathy and those on warfarin and/or corticosteroids, providing they do not have contra-indications. However, caution is advised when prescribing COXIBs for patients with risk factors for heart disease. These recommendations are very similar to those made by the National Institute for Clinical Excellence (NICE). In addition, it should be noted that for those patients without any cardiovascular complications but with gastrointestinal risk factors or on aspirin, it may be necessary to add a proton pump inhibitor (PPI). PPIs, however, provide little benefit for bleeding and ulceration of the lower intestine. One consequence of this low-grade bleeding is anaemia and a general feeling of malaise in patients with rheumatic disease. Current evidence suggests that COXIBs such as rofecoxib and celecoxib do not increase small intestinal permeability and that celecoxib does not cause lower intestinal bleeding and may be of benefit to those patients with lower gastrointestinal complications. In patients at risk for cardiovascular complications, both NSAIDs and COXIBs have been shown to increase the risk of myocardial infarctions (MI), hypertension and heart failure. Studies comparing COXIBs and non-specific NSAIDs should, however, be interpreted with caution. One needs to take into account the underlying baseline cardiovascular risk of the populations being compared. COXIBs appear to be prescribed preferentially to patients who were at an increased risk of cardiovascular events compared with patients prescribed non-specific NSAIDs. When the overall risk of cardiovascular complications is relatively low and an anti-inflammatory agent is required, current evidence suggests that celecoxib is an agent of choice because of its lower cardiovascular toxicity potential compared to NSAIDs and other COXIBs.

Review of the Cardiovascular Safety of COXIBs Compared to NSAIDS : Review Article

There is no doubt that NSAiDs and CoXiBS are the mainstay for managing pain and inflammation in arthritis. overall; at therapeutically equivalent doses; both NSAiDs and CoXiBs provide equivalent analgesic and anti-inflammatory efficacy. However; the gastrointestinal risk associated with NSAiDs is considerable. More recently; the cardiovascular risk associated with NSAiDs and CoXiBs has become a concern. Most patients; particularly the young; can benefit from NSAiDs without the risk of serious adverse gastrointestinal or cardiovascular events. However; patients with a previous history of serious gastrointestinal complications and the elderly; who could be at risk; do require alternatives. CoXiBs have significant benefits over NSAiDs in reducing the incidence of serious gastrointestinal complications (perforations; ulcers and gastric bleeding). Currently two oral CoXiBs are available; celecoxib and lumiracoxib; and one parenteral CoXiB; parecoxib. Celecoxib has been on the market for longer and has the largest body of evidence. The older NSAiDs; such as meloxicam; with preferential CoX-2 inhibition do not have good long-term evidence of reducing the incidence of serious gastrointestinal complications. However; these agents do have evidence of tolerability; ie; reducing the less-serious gastrointestinal effects; mainly dyspepsia. The South African Rheumatoid Arthritis Association's guidelines; amended in November 2005 recommend CoXiBs for elderly patients ( 60 years) with previous gastropathy and those on warfarin and / or corticosteroids; providing they do not have contra-indications. However; caution is advised when prescribing CoXiBs for patients with risk factors for heart disease. These recommendations are very similar to those made by the National institute for Clinical Excellence (NiCE). in addition; it should be noted that for those patients without any cardiovascular complications but with gastrointestinal risk factors or on aspirin; it may be necessary to add a proton pump inhibitor (PPi). PPis; however; provide little benefit for bleeding and ulceration of the lower intestine. one consequence of this low-grade bleeding is anaemia and a general feeling of malaise in patients with rheumatic disease. Current evidence suggests that CoXiBs such as rofecoxib and celecoxib do not increase small intestinal permeability and that celecoxib does not cause lower intestinal bleeding and may be of benefit to those patients with lower gastrointestinal complications. In patients at risk for cardiovascular complications; both NSAiDs and CoXiBs have been shown to increase the risk of myocardial infarctions (Mi); hypertension and heart failure. Studies comparing CoXiBs and non-specific NSAiDs should; however; be interpreted with caution. one needs to take into account the underlying baseline cardiovascular risk of the populations being compared. CoXiBs appear to be prescribed preferentially to patients who were at an increased risk of cardiovascular events compared with patients prescribed non-specific NSAiDs. When the overall risk of cardiovascular complications is relatively low and an anti-inflammatory agent is required; choice because of its lower cardiovascular toxicity potential compared to NSAiDs and other CoXiBs

Concept paper: establishment of a diagnostics platform for South Africa.

This concept paper focuses on diagnostics as one of the key areas of strategic importance. Lifelab intends to specialise in the research and development of in vitro diagnostic test systems specifically for diseases of relevance to the Southern African region. The use of diagnostic tests is an essential but costly element in the diagnosis and treatment of infectious diseases and in particular, HIV/AIDS. Consistent with the need to improve affordability and accessibility, the strategy will be to research, develop, and manufacture promising diagnostic test systems and through mutually beneficial partnerships with joint venture companies and distributors, rapidly introduce these diagnostic systems to the market.

Ventriculitis due to a hetero strain of vancomycin intermediate Staphylococcus aureus (hVISA): successful treatment with linezolid in combination with intraventricular vancomycin.

A 67-year male presented with relapse 14 days after treatment with vancomycin for a MRSA ventriculitis. CSF samples taken at the time of relapse grew MRSA with a MIC for vancomycin of 4 mg/L by E-test and therapy with linezolid (600 mg bd) and intraventricular vancomycin (20 mg od) was initiated. Using the macrodilution E-test, the isolate was found to have sub-populations with a MIC for vancomycin of 8 mg/L and teicoplanin of 12 mg/L and a population analysis profile almost identical to the hVISA strain MU3, indicative of a hVISA strain. Concentrations of vancomycin in the CSF over the period of therapy ranged from 25.6-192.5 mg/L after intraventricular administration and those of linezolid ranged from 3.4-6.7 mg/L after intravenous administration, exceeding the MICs for this isolate. The patient made a successful recovery, with no further episodes of ventriculitis at 1-year follow-up. We report the first case of ventriculitis due to hVISA. It was successfully treated with intrathecal vancomycin and intravenous linezolid. We also believe this to be the first documented case of clinical infection due to hVISA in South Africa.

Temperature-suitability maps for schistosomiasis in South Africa.

The results of parasitological surveys have shown that both urinary and intestinal schistosomiasis occur widely among the human residents of South Africa. The national data on both diseases have now been incorporated into a geographical information system, to develop new maps based on defined temperature constraints. The disease data, obtained from a 'hard-copy' atlas of schistosomiasis, were used as a template to select temperature regimes that were (1) suitable and (2) unsuitable for the transmission of schistosomes to humans in South Africa. The regimes were derived from the published results of investigations in which the biology of larval schistosomes (i.e. schistosome transmission) was related to temperature in South Africa. Those regimes that were based on the estimated temperature minima for transmission corresponded more closely to the disease-distribution data than those based on the corresponding maxima. An estimate of the number of children living in the climate-suitable areas was made but, within the context of the spatial methodology used and the limitations of the available disease data, it was not possible to predict the prevalences of schistosomiasis.

Comparison of the pharmacokinetic profiles of soluble aspirin and solid paracetamol tablets in fed and fasted volunteers.

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

AT1 receptor blockers--cost-effectiveness within the South African context.

OBJECTIVES: Hypertension is a leading chronic disease in South Africa, Significant mortality results from this condition and from stroke and ischaemic heart disease in which hypertension plays a major role. The objective of this study was to evaluate the evidence for the clinically effective and cost-effective treatment of hypertension, given that the clinician has decided to administer an AT1 receptor blocker. METHODOLOGY: A cost-effectiveness analysis was undertaken from the perspective of the funder of health care in the private sector. A predetermined protocol defined the study scope, the comparators (candesartan, losartan, valsartan and irbesartan) and the inclusion criteria for peer-reviewed data. Data for the clinical efficacy of the comparators, measured as the reduction (mmHg) in sitting diastolic blood pressure (SDBP) achieved, were extracted, statistically assessed and reported. The combinability of the data from different clinical trials was confirmed using analyses of variance. A pharmacoeconomic model was developed by combining these clinical results with South African retail prices and testing the results at a 95% confidence level. RESULTS: Significant difference in clinical effectiveness was found among the comparators, with the following mean reductions in SDBP observed: candesartan 10.57, irbesartan 9.07, losartan 8.89 and valsartan 7.11 mmHg. Candesartan was found to be significantly more effective than losartan. Valsartan was found to be less effective than the other 3 comparators. No significant difference was found between irbesartan and either candesartan or losartan. The reduction in SDBP per R100 spent indicated that candesartan was more cost-effective than the other comparators, among which there were no significant differences. Incremental savings of R5.0 million annually could be achieved by the funders of private health care for every 100,000 successfully treated patients using candesartan. CONCLUSION: Significant differences exist in both the clinical and cost-effectiveness measures used in this study for the comparators. The findings from the analysis will be valuable in decision-making processes for both the funders and providers of health care. This analysis can be enhanced further by the inclusion of additional clinical benefits and long-term health outcomes when the relevant data become available.

Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: novel PDE4 inhibitors.

A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v.