Nabil Al-Tawil

A phase I clinical study of a live attenuated Bordetella pertussis vaccine--BPZE1; a single centre, double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally to healthy adult male volunteers.

Background Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. Methods We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 103, 105 or 107 colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination. Results Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups. Conclusions BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups. Trial Registration ClinicalTrials.gov NCT01188512

Evaluation of safety and efficacy as an adjuvant for the chitosan-based vaccine delivery vehicle ViscoGel in a single-blind randomised Phase I/IIa clinical trial☆

ViscoGel, a chitosan-based hydrogel, has earlier been shown to improve humoral and cell-mediated immune responses in mice. In this study, a Phase I/IIa clinical trial was conducted to primarily evaluate safety and secondarily to study the effects of ViscoGel in combination with a model vaccine, Act-HIB to Haemophilus influenzae type b, administered as a single intramuscular injection. Healthy volunteers of both sexes, ages 22-50 and not previously vaccinated to HIB, were recruited. The trial had two phases. In Phase A, three ascending dose levels of ViscoGel (25, 50 and 75mg) were evaluated for safety in 3×10 subjects. Phase B had a single-blind, randomised, parallel-group design evaluating safety and efficacy in five groups, 20 subjects/group, comparing vaccination with 0.2μg or 2μg Act-HIB alone or combined with ViscoGel (50mg) and one group receiving the standard Act-HIB dose (10μg). No safety or tolerability concerns were identified. Local, transient reactions at the injection site were the most common adverse events. These were more frequent in groups receiving Act-HIB+ViscoGel, while other AEs were recorded at similar frequency in Act-HIB and Act-HIB+ViscoGel groups. Efficacy was evaluated by measuring serum anti-HIB antibodies and cellular responses in peripheral blood mononuclear cells (PBMC). There was a large variation in baseline anti-HIB antibody titres and no adjuvant effect was observed on the anti-HIB antibody production in groups vaccinated with Act-HIB+ViscoGel. ELISpot analyses revealed increased interferon-γ (IFN-γ) responses to Act-HIB in PBMCs from subjects vaccinated with Act-HIB in combination with ViscoGel, compared to groups receiving Act-HIB alone. Moreover, ViscoGel counteracted an inhibitory effect of Act-HIB vaccination on the IFN-γ response to both the vaccine itself and an irrelevant influenza antigen. In summary, ViscoGel was found to be safe and well-tolerated, supporting further examination of ViscoGel as a new innovative vehicle for vaccine development.

Patterns of age related changes for phosphodiesterase type-10A in comparison with dopamine D 2/3 receptors and sub-cortical volumes in the human basal ganglia: A PET study with 18 F-MNI-659 and 11 C-raclopride with correction for partial volume effect

ABSTRACT Phosphodiesterase 10A enzyme (PDE10A) is an important striatal target that has been shown to be affected in patients with neurodegenerative disorders, particularly Huntingtons disease (HD). PDE10A is expressed on striatal neurones in basal ganglia where other known molecular targets are enriched such as dopamine D2/3 receptors (D2/3 R). The aim of this study was to examine the availability of PDE10A enzyme in relation with age and gender and to compare those changes with those related to D2/3 R and volumes in different regions of the basal ganglia. As a secondary objective we examined the relative distribution of D2/3 R and PDE10A enzyme in the striatum and globus pallidus. Forty control subjects (20F/20M; age: 44±11y, age range 27–69) from an ongoing positron emission tomography (PET) study in HD gene expansion carriers were included. Subjects were examined with PET using the high‐resolution research tomograph (HRRT) and with 3T magnetic resonance imaging (MRI). The PDE10A radioligand 18F‐MNI‐659 and D2/3 R radioligand 11C‐raclopride were used. The outcome measure was the binding potential (BPND) estimated with the two‐tissue compartment model (18F‐MNI‐659) and the simplified reference tissue model (11C‐raclopride) using the cerebellum as reference region. The PET data were corrected for partial volume effects. In the striatum, PDE10A availability showed a significant age‐related decline that was larger compared to the age‐related decline of D2/3 R availability and to the age‐related decline of volumes measured with MRI. In the globus pallidus, a less pronounced decline of PDE10A availability was observed, whereas D2/3 R availability and volumes seemed to be rather stable with aging. The distribution of the PDE10A enzyme was different from the distribution of D2/3 R, with higher availability in the globus pallidus. These results indicate that aging is associated with a considerable physiological reduction of the availability of PDE10A enzyme in the striatum. Moreover as result of the analysis, in the striatum for both the molecular targets, we observed a gender effect with higher BPND the female group. Highlights18F‐MNI‐659 binding is a measure of Phosphodiestrease 10A enzyme availability.We examined the effect of age on 18F‐MNI‐659 binding in 40 healthy controls.Age related changes were also evaluated for 11C‐Raclopride and structural volumes.Patterns of molecular age related changes were evaluated with PVEc.We found an evident association between age and striatal 18F‐MNI‐659 binding.

In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects.

&NA; Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [18F]MNI‐659 was designed to measure the enzyme occupancy of PF‐02545920 in 8 healthy male volunteers (48 ± 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite‐corrected plasma input function for the quantification of [18F]MNI‐659 binding to PDE10A. The occupancy of PF‐02545920 was calculated with two different methods: In Method 1, [18F]MNI‐659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassens plot. Serum concentrations of PF‐02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF‐02545920 dose: 14–27% at 10 mg dose (N = 4) and 45–63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassens plot Method 2: 10 mg: 14–37%; 20 mg: 46–55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF‐02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202]. HighlightsSingle oral doses (10 mg, 20 mg) of PF‐02545920 were safe and well tolerated in healthy male volunteers.Enzyme occupancy of PF‐02545920 obtained using [18F]MNI‐659 PET was in the expected range.Striatal PDE10A occupancy increased with increasing PF‐02545920 dose and exposure, reaching ˜50% following the 20 mg single dose.A 20 mg oral dose of PF‐02545920 provides sufficient target brain occupancy for evaluation in future PDE10 clinical trials.

Effects of intranasal kinetic oscillation stimulation on heart rate variability

Kinetic oscillation stimulation in the nasal cavity (KOS) has been shown to have positive symptomatic effects in subjects with non‐allergic rhinitis and in patients with migraine.

Revisiting the Logan plot to account for non-negligible blood volume in brain tissue

BackgroundReference tissue-based quantification of brain PET data does not typically include correction for signal originating from blood vessels, which is known to result in biased outcome measures. The bias extent depends on the amount of radioactivity in the blood vessels. In this study, we seek to revisit the well-established Logan plot and derive alternative formulations that provide estimation of distribution volume ratios (DVRs) that are corrected for the signal originating from the vasculature.ResultsNew expressions for the Logan plot based on arterial input function and reference tissue were derived, which included explicit terms for whole blood radioactivity. The new methods were evaluated using PET data acquired using [11C]raclopride and [18F]MNI-659. The two-tissue compartment model (2TCM), with which signal originating from blood can be explicitly modeled, was used as a gold standard.DVR values obtained for [11C]raclopride using the either blood-based or reference tissue-based Logan plot were systematically underestimated compared to 2TCM, and for [18F]MNI-659, a proportionality bias was observed, i.e., the bias varied across regions. The biases disappeared when optimal blood-signal correction was used for respective tracer, although for the case of [18F]MNI-659 a small but systematic overestimation of DVR was still observed.ConclusionsThe new method appears to remove the bias introduced due to absence of correction for blood volume in regular graphical analysis and can be considered in clinical studies. Further studies are however required to derive a generic mapping between plasma and whole-blood radioactivity levels.