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Marihuana-derived material: distribution and effects after systemic administration
Abstract:
Studies have been made in an attempt to elucidate the mode of action of water-soluble marihuana-derived material (MDM). MDM lowers intraocular pressure (IOP) at systemic dose levels greater than 5 micrograms/rabbit by reducing aqueous humor inflow. Blood pressure, body temperature, and PO2 remain constant despite the wide variation in IOP caused by high dose levels of MDM, viz. an initial hypertensive phase followed by a hypotensive phase. Blood PCO2 and pH, however, both decrease with 1 mg MDM/rabbit indicating an acidosis which may partially explain some of the fall in IOP caused by MDM at this high dose level. Low doses of MDM (50 micrograms/animal), however, induce no such changes in systemic chemistry, illustrating the absence of an MDM effect which can explain the greater than 50% fall in IOP. Repeated injections of MDM on a weekly basis indicate a sequentially reduced effect on IOP. MDM, when incubated in vitro for 6 hours with saline, aqueous or vitreous, always induced a fall in IOP; incubation in these media for 24 hours, however, reduced the capacity to induce an IOP decrease. When aqueous or vitreous was removed from animals which had received intravitreal injections of MDM 24 hours previously (thus, at a time when the IOP in these animals was low) and was reinjected intravitreally into fresh recipient rabbits, the IOP fell in the recipients with aqueous, but not vitreous. Only when high doses of MDM (greater than or equal to 2 mg) were given systemically to a donor rabbit was any evidence obtained of a fall in IOP in recipient rabbits at short times after the donor injection (less than 10 min); at greater times after the donor injections whole blood or serum from donor rabbits failed to elicit a fall in IOP in recipient animals. These data indicate that, in vivo, MDM is bound or metabolized rapidly in rabbits when MDM is given systemically.
Insights
Water-soluble marihuana-derived material (MDM) effectively lowers intraocular pressure (IOP) by reducing aqueous humor inflow. However, its effects diminish with repeated use and rapid metabolism in vivo.
Area of Science:
- Ophthalmology
- Pharmacology
- Neuroscience
Background:
- Glaucoma treatment remains a significant challenge, necessitating novel therapeutic agents.
- Understanding the mechanism of action for existing treatments is crucial for optimizing efficacy and safety.
- Marihuana-derived material (MDM) has shown potential in lowering intraocular pressure (IOP).
Purpose of the Study:
- To elucidate the precise mode of action of water-soluble marihuana-derived material (MDM) in lowering intraocular pressure (IOP).
- To investigate the systemic and local effects of MDM on ocular physiology and systemic parameters.
- To assess the duration of action and potential for tolerance development with repeated MDM administration.
Main Methods:
- Systemic administration of varying doses of MDM to rabbits to measure IOP, blood pressure, body temperature, and blood gas levels.
- In vitro incubation of MDM with ocular fluids (aqueous and vitreous humor) followed by IOP assessment.
- Intravitreal injection of ocular fluids from MDM-treated animals into recipient rabbits.
- Systemic administration of MDM to donor rabbits followed by transfer of blood or serum to recipient rabbits.
Main Results:
- MDM significantly lowered IOP at systemic doses >5 µg/rabbit by reducing aqueous humor inflow.
- High-dose MDM induced transient systemic changes, including acidosis, while low doses had no systemic effects.
- Repeated MDM injections led to a diminished IOP-lowering effect, suggesting tolerance.
- In vitro, MDM reduced IOP after 6-hour incubation, but this effect decreased after 24 hours.
- Aqueous humor from MDM-treated rabbits retained some IOP-lowering capacity upon reinjection, unlike vitreous humor.
- Systemic MDM administration in donor rabbits only transiently affected recipient IOP, indicating rapid in vivo binding or metabolism.
Conclusions:
- MDM lowers IOP primarily by decreasing aqueous humor inflow.
- Systemic administration of MDM can induce transient physiological changes, particularly at higher doses.
- Tolerance to MDM's IOP-lowering effect develops with repeated administration.
- MDM appears to be rapidly metabolized or bound in vivo, limiting its sustained systemic effect.