Dr Frankel talks about his experience with prostate cancer therapies that have reduced his testosterone and the effect it has had on his life.
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With COVID, we have never been more aware of critical shortages of masks, ventilators, hospital beds, etc., all leading to rationing. In this BLOG, Dr Frankel, examines how rationing in our medical care is a much bigger problem than just face masks.
Here is an email from the patient with Myasthenia Gravis, who has done extremely well on combinations of CBD, THC and THC-A. The THC-A was clearly a huge part of it, but CBD was also of great benefit. So, here is her email:
Cookie Bekkar is a cancer survivor and patient of Dr Frankel's. She has created a website to share her story, what worked well for her and as a resource help inspire/educate other patients.
Dr Frankel talks about Trigeminal Neuralgia and the positive effect he has seen cannabis have on patients dealing with it. Some feedback received by three recent patients is also included.
There are "acid" and "neutral" forms of every cannabinoid molecule. Early man knew the difference and would either just eat the cannabis raw, or heat it to convert to the neutral or "active" forms of the cannabinoids.
The passive IgG transfer model of anti-MuSK myasthenia gravis was described previously 40 , 48 , 49 . Briefly, mice received daily injections of IgG from anti-MuSK-positive patient 4 (45 mg/day i.p., patient suffering grade 4B weakness – Myasthenia Gravis Foundation of America; IgG batch AM4.4). Passive transfer of IgG from this patient was previously reported to cause overt myasthenic weakness after 12 daily injections 50 .
Female C57BL/6 J mice (6–10 weeks) obtained from (Animal Resources Centre, Murdoch, WA Australia) were used in this study. Mice were killed with an overdose of pentobarbitone (30 mg intraperitoneal; CenVet Australia). All mouse experiments described in this paper were conducted with the approval of The University of Sydney Animal Ethics Committee (approval number K22/10-2011/3/5619) in compliance with the NSW Animal Research Act 1985 and the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes 7th Edition NH&MRC 2004. In relation to the collection of plasma, informed, written consent was obtained from patients in accordance with the Declaration of Helsinki (5th revision, 2004). The project was approved by the Human Research Ethics Committee of the Sydney South West Area Health Service.
WIN (10 µM) and AM630 (10 µM) caused no change in the area or density of postsynaptic nicotinic acetylcholine receptors (AChR) that might explain the increase in mEPP amplitude (Fig. 2a–e ; Supplementary Fig. S1 ). WIN also did not enhance mEPP amplitudes by prolonging the actions of acetylcholine in the synaptic cleft (Supplementary Fig. S2 ), a well-described effect of cholinesterase inhibitors. By exclusion, these results suggest that WIN acts presynaptically to increase quantal size. Since the amount of acetylcholine released from each synaptic vesicle cannot be measured directly, we instead tested the effect of drugs that block the filling of synaptic vesicles. Vesamicol (4 µM) inhibits the vesicular acetylcholine transporter, while bafilomycin (0.1 µM) blocks the H + -ATPase that is needed to drive the acetylcholine transporter 24 , 25 . Neither of these drugs on their own affected mEPP amplitudes in our recordings (Supplementary Fig. S3a and see refs 24 , 25 ), but both inhibitors blocked the WIN-induced increase in mEPP and EPP amplitudes (Fig. 2f , Supplementary Fig. S3 ). Thus, the cannabinoid-induced increase in quantal amplitude appears to depend upon the active transport of acetylcholine into synaptic vesicles. Consistent with enhanced vesicle filling, electron microscopy revealed an increase in synaptic vesicle diameter after WIN treatment 26 (Fig. 2g–i ; 43.9 nm vs 47.4 nm; P < 0.01). Assuming spherical geometry, this equates to a 48% increase in vesicle volume (Fig. 2j ; see Methods and Supplementary Table 1 ). Together, our results strongly suggest that WIN acutely enhances neuromuscular transmission by increasing the loading of synaptic vesicles within the presynaptic nerve terminal.
3 mm custom-made single monopolar recording electrodes were glued to the surface of the skin: one over the dorsal aspect of the gastrocnemius muscle and the second electrode at the ankle of the same hind limb. Electrolyte gel (VIASYS Healthcare, Madison, USA) was applied directly at the electrode sites. Stimulation of the sciatic nerve was accomplished via a 4 mm incision in the sciatic notch and by placing the nerve on custom-made silver hook electrodes (0.6 mm diameter). Ten stimuli were delivered at 3 impulses/sec and three such trains recorded from each muscle were averaged.
This work was supported by the Brain Foundation and Australian Myasthenic Association in New South Wales (to SWR), and Australian Research Council (DP0988227 to DAP). We thank Drs Louise Cole (Advanced Microscopy Facility, Bosch Institute) and Shanker Karunanithi for technical advice and assistance, Joshua A. Way, who performed some mEPP and EPP recordings, the molecular medicine laboratory at Concord Hospital, the apheresis team, Sr Beth Newman, Louise Wienholt and patients from around Australia who contributed their plasma to this research, and Prof Mark Connor for critical comments on the manuscript.
The diaphragm with the phrenic nerve attached was quickly dissected, pinned on a Sylgard-coated dish and bathed in oxygenated Ringer’s solution containing physiological calcium levels (in mM: NaCl-136, KCl-5, NaH2PO4-1, NaHCO3-12.8, MgCl2-1, CaCl2 and glucose-10, pH adjusted to 7.3). Spontaneous miniature endplate potential (mEPP) and nerve-evoked endplate potential (EPP) recordings were made at room temperature as previously described 28 , 40 . Contraction was blocked using the muscle sodium channel blocker, µ-conotoxin GIIIb (1 μM μCTX, Peptide Institute, Japan). EPP and mEPP recordings were started 1–2 hrs after the diaphragm was placed in the bath solution. Spontaneous mEPP amplitudes were recorded for 1–3 min and were normalized to a resting potential of −80 mV. A train of 40 stimuli (1 Hz) was used for EPP analyses (average amplitude; 20 stimuli for the vesamicol and bafilomycin experiments). EPP amplitudes were normalized to −80 mV and then corrected for non-linear summation 41 . Quantal content was calculated by dividing the normalized and corrected EPP amplitudes by the normalized mEPP amplitude for each muscle fiber. Recordings were made from 12–18 muscle fibers from each muscle to derive mean mEPP and EPP values for each sample. Only fibers with a stable resting membrane potential (RMP) ≤ −60 mV were analyzed. To calculate the 90–10% decay times before and after pyridostigmine treatment the average decay time for all sample traces (irrespective of peak amplitude) for n = 3–4 mice was compared.
Endplate potential recordings
Cannabinoid drugs have already been approved for the treatment of nausea in chemotherapy patients and clinical trials are underway to test for treatment of spasticity and other muscle-debilitating symptoms of multiple sclerosis 35 – 37 . The increasing usage of cannabinoids in a variety of medical conditions 38 , 39 highlights the crucial need to better understand the physiological roles of cannabinoids in the periphery. Here we reveal evidence of their involvement in regulating neuromuscular transmission, and a possible therapeutic potential for cannabinoid signaling in myasthenia gravis.
Supplementary information accompanies this paper at 10.1038/s41598-018-22888-4.