Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs

Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56 mg/kg were intravenously infused over 10 min (n = 4 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs.     

HIV cure: global overview of bNAbs’ patents and related scientific publications

Introduction: This article provides a global overview of patent deposits for broadly neutralizing antibodies (bNAbs), which have emerged as a key strategy for HIV cure and future HIV vaccines. Scientific and technological barriers to the discovery of an effective HIV vaccine in the last 40 years have raised concerns on the potential for relevant advances in this area. Nevertheless, recent breakthrough studies have identified novel immune pathways for new innovative HIV vaccine and HIV cure strategies.

Areas covered: In our patent study, we have identified in a global scale, in the last decade, a sharp increase in the number of bNAbs’ patent deposits related to HIV prevention and treatment strategies, reaching 90 bNAbs in 2017, protected by 184 different patent deposits. Refining our patent search to the different stages of bNAbs’ development has also allowed us to identify 12 of them already at clinical stage of research (VRC01, 10E8, 3BNC117, 10-1074, 2G12, 2F5, KD-247, 4E10, PG9, PGDM1400, PGT121, and VRC07). We describe these recent breakthroughs and discuss the prospects and limitations of these novel strategies.

Expert opinion: Our results indicate the intellectual property outcomes of a scientific revolution in this field, expressing innovative modifications in antibodies to increase their potency and half-life, which have resulted in extremely potent antibodies that could provide novel preventive and therapeutic HIV strategies.     

A stepwise increase in pharmacotherapy depending on the severity of COPD

The overall approach to managing stable COPD should be characterized by a stepwise increase in treatment, depending on the severity of the disease in accordance with JRS COPD guideline. None of the existing medications has been shown to modify the long term decline in lung function that is the hallmark of this disease. Therefore, pharmacothepary for COPD is used to decrease symptoms and/or complications. Smoking cessation and influenza vaccines are the base of pharmacotherapy. And the principal short and long acting bronchodilator treatments are anticholinergics, beta2-agonists, methylxanthines, and a combination of one or more of these drugs. And regular treatment with inhaled glucocorticosteroids should only be prescribed for symptomatic COPD patients with a documented spirometric response to glucocorticosteroids or for those with stage III and repeated exacerbations.     

Independent evolution of pyrimethamine resistance in Plasmodium falciparum isolates in Melanesia

Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.     

Mandibular widening by intraoral distraction osteogenesis for severe telescopic bite correction: a report of 2 cases

Two patients with telescopic bites due to narrow mandibular arches were treated by mandibular widening and mandibular lengthening with intraoral distraction osteogenesis. Both patients underwent distraction osteogenesis surgery successfully, without any complications. The amount of widening in the 2 cases was 6 mm and 5 mm, and the intercanine distance increased by 2.1 mm and 4.9 mm, respectively. Nonextraction orthodontic treatment was performed after removal of the distraction devices in both cases. The postsurgical orthodontic treatment periods of the 2 cases were 13 months and 7 months, respectively. Eventually, functional occlusions and good profiles were obtained in both cases. Although both patients complained of temporomandibular joint symptoms at the first consultation, those symptoms were improved after treatment. At 3 years after debonding, dentofacial relapse was negligible. In conclusion, mandibular widening by intraoral distraction osteogenesis appeared to be an effective modality for correcting telescopic bites.