Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency ...of the von Willebrand factor–cleaving protease (ADAMTS13) has been demonstrated, but additional genetic and/or environmental triggers are thought to be required to incite acute illness. Here we report that 4 days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers because injections with an inhibitory monoclonal antibody (mAb) consistently (n = 6) induced severe thrombocytopenia (< 12 × 109/L), microangiopathic hemolytic anemia, and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet- and von Willebrand factor–rich thrombi in kidney, heart, brain, and spleen but not lungs. Prolonged inhibition (14 days, n = 1) caused myocardial ischemic damage and asplenia but not death. Control animals (n = 5) receiving equal doses of a noninhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Furthermore, we present a reliable animal model of this disease as an opportunity for the development and validation of novel treatment strategies.
Abstract Background In designing a training program in transfusion medicine, a range of factors needs to be taken into account. One of these is delineating the scope of practice of students in order ...to ensure a program that will be appropriate in terms of content, level of difficulty, and the requirements of the student's working environment. Very little has been done in terms of scientifically studying the differences in scope of practice of a specialist in transfusion medicine compared to a clinician who deals with blood transfusion on an intermittent basis. Study design and methods A formal qualitative and semi-quantitative research approach was followed to determine and test the factors considered important in determining the difference in scope of practice between a specialist in transfusion medicine and the clinician who deals with transfusion on an ad hoc basis, and consisted of a literature survey, followed by semi-structured interviews and a Delphi survey. Results Nineteen factors were identified, through semi-structured interviews, as being particularly descriptive of the scope of practice of a full-time specialist in transfusion medicine that differentiated them from clinicians dealing with blood transfusion on an ad hoc basis. Nine factors were identified as being descriptive of the scope of practice of clinicians dealing with blood transfusion on an ad hoc basis, which differentiate them from full-time specialists in transfusion medicine. Conclusion Designing a training program with the end in mind requires an understanding of the variable contexts within which clinicians, who deal with blood transfusion, work. The findings of this study provide a framework for planning a curriculum that takes such differing scopes of practice into account.
The most difficult of arts Louw, Vernon J.; Ntusi, Ntobeko A.B.
South African medical journal,
10/2019, Volume:
109, Issue:
10
Journal Article
Peer reviewed
Open access
In 1902 William Osler wrote in his essay, ‘Chauvinism in medicine’, that it is the ambition of the physician ‘To wrest from nature the secrets which have perplexed philosophers in all ages, to track ...to their sources the causes of disease, to correlate the vast stores of knowledge, that they may be quickly available for the prevention and cure of disease.
To assess the rates of vascular thrombotic adverse events in the first 35 days after one dose of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in healthcare workers in South Africa and to ...compare these rates with those observed in the general population.
Open label, single arm, phase 3B study.
Sisonke study, South Africa, 17 February to 15 June 2021.
The Sisonke cohort of 477 234 healthcare workers, aged ≥18 years, who received one dose of the Ad26.COV2.S vaccine.
Observed rates of venous arterial thromboembolism and vaccine induced immune thrombocytopenia and thrombosis in individuals who were vaccinated, compared with expected rates, based on age and sex specific background rates from the Clinical Practice Research Datalink GOLD database (database of longitudinal routinely collected electronic health records from UK primary care practices using Vision general practice patient management software).
Most of the study participants were women (74.9%) and median age was 42 years (interquartile range 33-51). Twenty nine (30.6 per 100 000 person years, 95% confidence interval 20.5 to 44.0) vascular thrombotic events occurred at a median of 14 days (7-29) after vaccination. Of these 29 participants, 93.1% were women, median age 46 (37-55) years, and 51.7% had comorbidities. The observed to expected ratios for cerebral venous sinus thrombosis with thrombocytopenia and pulmonary embolism with thrombocytopenia were 10.6 (95% confidence interval 0.3 to 58.8) and 1.2 (0.1 to 6.5), respectively. Because of the small number of adverse events and wide confidence intervals, no conclusions were drawn between these estimates and the expected incidence rates in the population.
Vaccine induced immune thrombocytopenia and thrombosis after one dose of the Ad26.COV2.S vaccine was found in only a few patients in this South African population of healthcare workers. These findings are reassuring if considered in terms of the beneficial effects of vaccination against covid-19 disease. These data support the continued use of this vaccine, but surveillance is recommended to identify other incidences of venous and arterial thromboembolism and to improve confidence in the data estimates.
ClinicalTrials.gov NCT04838795.
Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these ...enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin rifampin) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib.
Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments.
Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib.
In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.
Abstract Cytopaenias, especially anaemia, are common in the HIV-infected population. The causes of HIV related cytopaenias are multi-factorial and often overlapping. In addition, many of the drugs ...used in the management of HIV-positive individuals are myelosuppresive and can both cause and exacerbate anaemia. Even though blood and blood products are still the cornerstone in the management of severe cytopaenias, how HIV may affect blood utilisation is not well understood. The impact of HIV/AIDS on blood collections has been well documented. As the threat posed by HIV on the safety of the blood supply became clearer, South Africa introduced progressively more stringent donor selection criteria, based on the HIV risk profile of the donor cohort from which the blood collected. The implementation of new testing technology in 2008 which significantly improved the safety of the blood supply enabled the removal of what was perceived by many as a racially based donor risk model. However, this new technology had a significant and sustained impact on the cost of blood and blood products in South Africa. In contrast, it would appear little is known of how HIV influences the utilisation of blood and blood products. Considering the high prevalence of HIV among hospitalised patients and the significant risk for anaemia among this group, there would be an expectation that the transfusion requirements of an HIV-infected patient would be higher than that of an HIV-negative patient. However, very little published data is available on this topic which emphasises the need for further large-scale studies to evaluate the impact of HIV/AIDS on the utilisation of blood and blood products and how the large-scale roll-out of ARV programs may in future play a role in determining the country's blood needs.
Despite the challenges of a resource-limited environment, the outcome of chronic myeloid leukaemia (CML) patients in South Africa is similar to that in developed countries, thanks to access to ...tyrosine kinase inhibitors through patient assistance programmes and clinical trials. A number of challenges are faced in terms of reimbursement of drugs, simultaneous co-infection with human immunodeficiency virus, access to allogeneic stem cell transplantation and, until recently, a lack of local recommendations appropriate for our setting. It is hoped that the newly published recommendations for the management of CML in South Africa will close many of the gaps in knowledge and practice and thus translate into better patient outcomes. Epidemiological data are limited and there is a need for more collaborative studies locally to elucidate issues such as incidence, prevalence and response to treatment. The challenges experienced in the management of CML and other cancers in the developing world are often economical and political in nature and require a comprehensive approach by clinicians, pathologists, health economists, medical insurers and policy makers if we are to find sustainable solutions.
Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer with a substantial risk of metastasis which causes clinical treatment failure. This study investigated the anti-CSCC ...effects of a triterpenoid compound, Cucurbitacin B (CuB). Dose-response studies showed that CuB inhibited 50% growth (ED50) of the CSCC cell lines (SRB1, SRB12, SCC13, COLO16) in liquid culture at 4 x 10(-7)-10(-5) M. Soft-agar assays demonstrated that nearly all of the CSCC clonogenic cells were inhibited at 10(-7) M CuB. FACS analysis found that the compound (10(-7) M, 48 h) caused G2/M arrest. The CSCC cells underwent profound morphologic changes within 60 min after exposure to CuB (10(-7) M), rounding up and losing their pseudopodia. CuB (10(-7) M) caused prominent multinucleation of the cells after they were pulse-exposed (24 h) to the drug, washed and cultured in normal medium for an additional 24 h. The drug (10(-8)-10(-6) M, 3-24 h) decreased levels of CDC2 and cyclin B1 in SRB1 and SRB12 cell lines as seen by Western blot analysis. Migration of SRB1 and SRB12 cells was inhibited by 10(-7) M CuB. Interestingly, CuB synergistically potentiated the anti-proliferative effect of cisplatin in CSCC. In summary, CuB has a prominent anti-proliferative activity on CSCC cells. In vivo studies and clinical trials of this drug should be pursued in CSCC.
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