PKG activators(Merck)

The second messenger cyclic nucleotides cAMP and cGMP are key effectors of thermogenesis in adipocytes in response to a diverse array of cues. Their intracellular levels are normally regulated by the hydrolytic action of phosphodiesterases (PDEs), a conserved superfamily of enzymes composed of 12 families in humans (PDE1‐12) with distinct substrate specificities and tissue distribution profiles. Phosphodiesterase inhibitors are thus promising drugs for the treatment of metabolic disease by promoting cyclic nucleotide‐mediated adipose tissue thermogenesis, but so far mainly those that elevate either cAMP or cGMP signaling alone have been studied. We previously showed that inhibition of the dual‐specificity phosphodiesterase type 10A (PDE10A) with the small molecule drug MP‐10 sufficiently induces a thermogenic gene expression program in differentiated human white pre‐adipocytes (HWP‐ds) to a similar degree as combined cAMP and cGMP treatment. Here, we asked (1) which PDE10A isoforms are expressed in HWP‐ds, (2) the downstream signaling pathways PDE10A controls, and (3) how PDE10A expression is influenced by inflammatory stimuli in this cell type. Immunoblot analysis revealed that both the cytosolic (PDE10A1) and membrane‐bound (PDE10A2) isoforms of PDE10A are highly expressed in HWP‐ds, predominantly in the former subcellular compartment. This was confirmed by fractionation and immunofluorescence analyses. Inhibition of PDE10A with MP‐10 dose‐dependently increased PKA and PKG signaling as revealed by phosphorylation of cyclic response element binding protein (CREB) and vasodilator‐stimulated phosphoprotein (VASP) at S133 and S239, respectively. Consistently, the stimulation of lipolysis by MP‐10 was fully prevented by combined pre‐incubation of HWP‐ds with selective PKA and PKG inhibitors. Finally, mimicking the adipose tissue microenvironment in obesity by applying pro‐inflammatory cytokines onto HWP‐ds caused an early (4‐hour) and sustained (24‐hour) increase in PDE10A mRNA expression. These results provide new insight into the molecular character, function, and regulation of PDE10A in human adipocytes and further justify the use of selective inhibitors for the treatment of metabolic disease through stimulating adipose tissue thermogenesis in a more efficient and targeted manner.

To develop an effective, patient-centred and sustainable service, we set up a virtual clinic (VC) for patients with Parkinson's disease, combining phone consultations and reports from wearable technology. The Parkinson's Kinetigraph (PKG) is a wrist-worn device providing objective motor assessment, generating a report used by clinicians to optimise medication regimens.

A pilot study of VC was designed using quality improvement methodology. For a VC appointment, patients were phoned by a clinician. After discussing symptoms and reviewing the PKG report, the clinician could decide on any medication changes or other interventions and relay this to the patient's general practitioner in a clinic letter. Patient feedback was gathered via questionnaires and data collected on the outcomes and timings of the consultations.

Over 12 clinics, 61 patients had VC appointments. Of questionnaire respondents, 89% were satisfied with VC (n=41). At VC, the clinician was able to make a treatment decision comparable to a face-to-face clinic in 79% of cases (n=48). Reasons appointments were deemed unsuccessful included issues with the PKG, speech or hearing problems and complex phase of disease. VC appointments, including administration time, last on average 22 min. This compares to 20 min face-to-face appointments but these do not include administration time.

We have demonstrated a safe and effective VC template. Most VC appointments are equivalent to face-to-face clinic in terms of treatment outcome. Success could be further improved by appropriate patient selection. Using VC is time saving and can result in releasing face-to-face appointment slots for those in urgent need or newly referred patients. Further cost analysis is required; the cost of the PKG alone is more expensive than a face-to-face appointment, but this does not take into account other value added, such as patient convenience and satisfaction, and reduced need for ambulance transport.