Certain mutations in the dystrophin gene disrupt the reading

frame, leading to little or no dystrophin production and the severe clinical

features seen in Duchenne muscular dystrophy (DMD). However, when the reading

frame is preserved—even if parts of the protein are missing—muscle function is

partially maintained, as observed in Becker muscular dystrophy.

How do antisense oligonucleotide therapies exploit this

difference to improve outcomes in patients with DMD?

Eli Lilly decided to test all four lead compounds in Phase I clinical trials and the following pharmacokinetic parameters were determined.

Table 4: Pharmacokinetic properties of lead compounds as determined in Phase I clinical trials

Based on the data provided in Table 4, which of the compounds would be predicted to have the highest lipophilicity?

Mutations in RPE65 impair the visual cycle in retinal cells,

leading to early-onset vision loss. An AAV-mediated gene therapy delivers a

functional copy of RPE65 to retinal tissue. This results in in sustained

protein expression and lasting visual improvement following a single administration;

even though no permanent changes are made to the patient’s genome.

Which characteristic of the AAV delivery system most

directly accounts for this durable therapeutic benefit?

In pre-clinical studies, Eli Lilly tested four lead compounds for efficacy as selective serotonin reuptake inhibitors, using both in vitro and in vivo assays in rodents.

Initial studies investigated in vitro efficacy and selectivity.

Table 1: Assessment of in vitro efficacy of lead compounds in rodents

Inhibition of 5-HT uptake was assessed using synaptosomal preparations of rat brain, and affinity of binding to α₁-adrenoceptors was assessed using membrane preparations of rat cerebral cortex.

IC₅₀ = half maximal inhibitory concentration

The beta-adrenoceptor antagonist, metoprolol is metabolised almost exclusively by CYP2D6.  

Which of the following would MOST LIKELY occur if metoprolol is taken at the same time as diphenhydramine (Benadryl), a known CYP2D6 inhibitor?

The following information is relevant to this question:

Approximate volumes of body compartments

• Plasma volume                           ~0.05 L/kg
• Total extracellular volume           ~0.2 L/kg
• Total body water                         ~0.55 L/kg

The Vd of a drug is determined to be 0.18 L/kg.  Which of the following statements is MOST consistent with this Vd?  The drug is:

During lead optimisation, all lead compounds were evaluated for carcinogenic effects using the Ames test. 

Table 3:  Assessment of growth of his- salmonella in histidine free media in the absence or presence of liver extract.

++ = colony growth

Based upon the data shown above in Table 3, which of the following compounds only has mutagenic potential in its active, non-metabolised form?

During lead optimisation, all lead compounds were evaluated using the forced swim test in mice. 

Table 2: Assessment of in vivo efficacy of lead compounds in rodents

In the forced swim test, decreased immobility is considered to be associated with antidepressant activity 

Values given as mean ± SEM

Based upon the data shown in Table 2, which of the compounds is MOST LIKELY to be effective in the treatment of patients with severe depression?

A 75-year-old woman with poor kidney function is prescribed

a painkiller that is normally removed from the body by renal clearance. The

doctor decides to give the drug less frequently than the standard dosing schedule.

Why is it appropriate to increase the time between

doses in this patient?

In pre-clinical studies, Eli Lilly tested four lead compounds for efficacy as selective serotonin reuptake inhibitors, using both in vitro and in vivo assays in rodents.

Initial studies investigated in vitro efficacy and selectivity.

Table 1: Assessment of in vitro efficacy of lead compounds in rodents

Inhibition of 5-HT uptake was assessed using synaptosomal preparations of rat brain, and affinity of binding to α₁-adrenoceptors was assessed using membrane preparations of rat cerebral cortex.

IC₅₀ = half maximal inhibitory concentration