Antibiotic Resistance

By: Ph. Ali Al-Mehanna

 

Antimicrobial resistance is when microorganisms (i.e. bacteria, viruses, fungi, and parasites) become either less susceptible or completely immune to antimicrobial drugs (i.e. antibiotics, antivirals, antifungals, antimalarials, and anthelmintics). New resistance mechanisms are emerging globally, putting us at risk of failing to treat common infectious diseases. As a result, common infections are causing prolonged illness, disability, and death; hence, resistant microorganisms are commonly referred to as “superbugs”.

 
This is going to be the first part of a series of articles exploring antimicrobial resistance; and in this part, we begin by exploring some of the molecular mechanisms of antimicrobial resistance and their relative examples. There are two main factors driving antimicrobial resistance: evolution and clinical/environmental practices. This evolution is aided by poor healthcare practice by health professionals and agricultural use of antibiotics indiscriminately. There are multiple mechanisms by which antimicrobial resistance develops, and they are as follows in no specific order:

 
1) Reduced entry of the antibiotic into the pathogen

Gram negative bacteria have an outer membrane that acts as a permeable barrier preventing large polar molecules from entering the cell. Many antibiotics are small polar entities that are capable of entering the cell through small protein channels called porins. Thus, antimicrobial drug concentrations can be affected markedly depending on the nature of these porins. Therefore, when there is a loss of, absence of, or mutation in a favored porin channel, the drug entry into the cell is slowed or even stopped all together. As such, if the drug requires active transport across the cell membrane, a phenotypic change or mutation that can slow this transport mechanism, can lead to resistance. An example of this mechanism is seen with melarsoprol in the treatment of Trypanosoma brucci disease (also known as Sleeping Sickness). Melarsoprol requires trypanosome P2 protein transporter (porin) to enter through the parasite wall. However, when the parasite either lacks or has a mutant P2 transporter protein, resistance to melarsoprol occurs.

 

2) Resistance due to drug efflux

Efflux pumps on the cytoplasmic membrane of cell walls can expel antibiotics out of the cell as an evolutionary defense mechanism. Microorganisms can be less susceptible to antimicrobics by overexpressing specific efflux pumps, of which there are 5 major types: the multidrug and toxic compound extruder (MATE); the major facilitator superfamily (MFS) transporters; the small multidrug resistant (SMR) system; the resistance nodulation division (RND) exporters; and the ATP binding cassette (ABC) transporters. Antimalarial drugs have faced tragic resistance by the Plasmodium falciparum parasite. A point mutation in the plasmodium flaciparum multidrug resistance gene 1 (Pfmdr1) creates the ABC transporter leading to drug resistance and failure of chemotherapy. Unfortunately, this mechanism of drug resistance is seen with most antimalarial drugs.

 

3) Resistance due to destruction of antibiotic

This is one of the most commonly known mechanisms of antimicrobial resistance. Aminoglycosides and B-lactam are two prominent antibiotics that suffered bacterial resistance by inactivation or destruction. The destruction is seen when strains of bacteria are able to produce aminoglycoside-modifying enzyme and b-lactamase that degrade aminoglycosides and b-lactams, respectively.

 

References

• Hilal-Dandan, R., & Brunton, L. (2013). Goodman and Gilman manual of pharmacology and therapeutics. McGraw Hill Professional.
• Garneau-Tsodikova, S., & Labby, K. J. (2016). Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives. MedChemComm, 7(1), 11-27.
• Kennedy, P. G. (2008). The continuing problem of human African trypanosomiasis (sleeping sickness). Annals of neurology, 64(2), 116-126.
• Ventola, C. L. (2015).The antibiotic resistance crisis: part 1: causes and threats. Pharmacy and Therapeutics, 40(4), 277.

 

Complementary medicine: Ginko Biloba

By: Ph. Ali Al-Mehanna

 

Scientific / botanical name
Ginkgo biloba. Family: Ginkgoaceae.

 

Alternative names:
Fossil Tree, Ginkgo Biloba Leaf, Ginkgo Folium, Graine de Ginkgo, Herba Ginkgo Biloba, Japanese Silver Apricot, Kew Tree, Maidenhair Tree, Noyer du Japon, Pei Go Su Ye, Salisburia Adiantifolia, Yen Xing, Yinhsing.

 

Dosage forms:
Orally: tablet, capsules and lozenges.

 
Action:
● Ginkgo leaf might work by protecting tissues from oxidative damage. Ginkgo leaf flavonoids have antioxidant and free radical scavenging properties. The flavonoids seem to prevent or reduce cell membrane lipid peroxidation, and decrease oxidative damage to erythrocytes.
● Ginkgo’s flavonoids also protect neurons and retinal tissue from oxidative stress, and injury following ischemic episodes. Protecting neurons and other tissues from oxidative damage might prevent progression of tissue degeneration in patients with dementia and other conditions.

 
Indications:
● Cognitive impairment and dementia (Alzheimer’s, vascular or mixed dementia)
● Tinnitus
● Peripheral vascular disease
● Anxiety

 
Adverse effects:
● Few cases of gastrointestinal upset, headaches and dizziness were reported.
● Rare case reports of subarachnoid haemorrhage, subdural haematoma, intracerebral
haemorrhage, subphrenic haematoma, vitreous haemorrhage and postoperative bleeding have been documented.

 
Dosage:
● A standardised extract of Ginkgo biloba leaves is a well-defined product and contains approximately 24% flavone glycosides and 6% terpene lactones.
● Products containing EGb761 extract should contain 24% ginkgo flavone glycosides and 6% terpenoids.
Common dose range: Tablets/capsules: 80–240 mg daily of a 50:1 standardised leaf extract in two or three doses has been used in studies.
Dementia syndromes: 120-240 mg per day of ginkgo leaf extract, divided in two or three doses, has been used.
Peripheral vascular disease: 120-240 mg per day of ginkgo leaf extract (EGb 761, Tanakan, Ipsen), divided into two or three doses, has been used; however, the higher dose may be more effective.
Vertigo or tinnitus: 120-160 mg per day of ginkgo leaf extract, divided into two or three doses, have been used.

 

Drug / Disease interactions:
● Anticoagulants (e.g. warfarin), antiplatelet drugs (e.g. aspirin, clopidogrel) and NSAIDs (e.g. ibuprofen): Case reports suggest that concurrent use with drugs that increase clotting time or inhibit platelet function may increase the risk of bleeding, particularly in the older patient. Monitor for bruising or overt bleeding.
● Antiepileptics and seizure threshold–lowering drugs (e.g. prochlorperazine, chlorpromazine): Seizures have been reported in patients taking ginkgo who are predisposed to seizures or on medications that lower the seizure threshold.
● Antipsychotics (e.g. haloperidol, olanzapine) : may reduce the sexual dysfunction side-effects of these drugs and improve sleep continuity; however, results from clinical studies are mixed; possible beneficial interaction.
● Cytochrome P450 substrates : Studies suggest that ginkgo may mildly inhibit CYP1A2, CYP2D6, CYP2E1 and CYP2C9, and induce CYP2C19.

 

Contraindications /precautions:
● If unusual bleeding or bruising occurs, stop use immediately. It may be prudent to suspend use for 1 week prior to major surgery.
● Recent, rare case reports have suggested that ginkgo should be used with caution in people with known risk factors for cerebral haemorrhage and epilepsy until further investigation can clarify its safety.

 
Specific considerations:
● Can cause major bleeding, including subarachnoid haemorrhage.
● Has been reported to increase plasma insulin concentrations in healthy volunteers and decrease insulin concentrations in subjects with type 2 diabetes.

 
Use in:
Pregnancy: theoretically, ginkgo could adversely affect pregnancy as a result of changes in bleeding. Avoid use, as there are insufficient reliable safety data.
Breastfeeding: Insufficient reliable data. Avoiding use is recommended.

 
Evidence for use:
A Cochrane review of RCTs published to September 2007 investigating use of Ginkgo biloba in people with acquired cognitive impairment (including dementia) of any degree of severity found that many of the early trials used unsatisfactory methodology. Subgroup analysis of patients with Alzheimer’s disease (925 from nine trials) showed no consistent pattern of benefit. Most trials studied the standardised extract EGb761.

 
A 2004 Cochrane review of controlled trials identified only three good-quality trials and found no evidence that gingko is effective for tinnitus.

A 2000 meta-analysis of eight RCTs found that Gingko biloba extract (120–160 mg daily) was superior to placebo for the treatment of intermittent claudication. The size of the overall treatment effect was modest and of uncertain clinical relevance.

 
A 2004 systematic review of nine RCTs found that, in the majority of the studies, the standardised ginkgo extract EGb761 increased pain-free walking distance compared with placebo.

 
However, an RCT involving 62 older adults found that 300 mg daily of EGb761 does not significantly improve maximum treadmill walking time in patients with peripheral arterial disease.


Counselling and practice points:

You might experience some side effects, such as gastrointestinal upset, headache, bruising and major bleeding,
while taking this medicine.
Consider stopping before planned surgery (including dental extraction); seek medical advice.
Ginkgo can take up to 4–12 weeks to provide its maximum benefit.

 

Additional resources:
● Pharmaceutical Society of Australia. (2012). Australian pharmaceutical formulary and handbook. (22nd
ed..). Curtin, ACT: Pharmaceutical Society of Australia.
● GINKGO Monograph: Natural Medicines Comprehensive Database. (n.d.). Retrieved May 28, 2015, from
http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx?cs=CEPDA&s=ND&pt=100&id=333&ds=effective

 

References

  • Birks, J., & Grimley Evans, J. (2002). Ginkgo biloba for cognitive impairment and dementia. The Cochrane Library.
  • Hilton, M. P., & Stuart, E. L. (2004). Ginkgo biloba for tinnitus. The Cochrane Library.
  • Pittler, M. H., & Ernst, E. (2000). Ginkgo biloba extract for the treatment of intermittent claudication: a metaanalysis of randomized trials. The American journal of medicine, 1 08 (4), 276-281.
  • Horsch, S., & Walther, C. (2004). Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD)–a review based on randomized, controlled studies. International journal of clinical pharmacology and therapeutics, 42 (2), 63-72
  • Gardner, C. D., Taylor-Piliae, R. E., Kiazand, A., Nicholus, J., Rigby, A. J., & Farquhar, J. W. (2008). Effect of
  • Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial. Journal of cardiopulmonary rehabilitation and prevention, 28 (4), 258

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

By Ph. Yasmeen Rafique

 

A new class of lipid lowering agents to be used as an adjunct to statins

 

PCSK9 is primarily synthesized, secreted and expressed in the liver, where it binds to LDLRs in the hepatocellular membrane to form a complex. The PCSK9/LDLR complex then enters the endosomal system where it is eventually degraded in the lysosomes, hence, preventing the transportation of LDLR to the cell surface. Therefore, increased levels of PCSK9 can inhibit LDLR recycling to the cell surface which in turn increases the low-density lipoprotein-cholesterol (LDL-C) levels in the blood. PCSK9 inhibitors, such as human IgG2 monoclonal antibodies (mAbs), target PCSK9 to prevent it from binding to the LDLR and hence result in increased LDLR expression, which eventually lead to increased hepatic uptake of LDL-C, reducing LDL-C levels in the blood.

 

Patients with familial hypercholesterolemia (FH) are sometimes unable to achieve normal LDL-C levels, even when they are treated with the maximum dose of statins mainly due to an increase in the transcription of PCSK9 upon using statins in these patients. Therefore, PCSK9 inhibitors are promising therapeutic targets for the treatment of FH and might improve the efficacy of statins in such patients. Three mAbs against PCSK9 have been developed. These include Alirocumab (REGN727/SAR236553) developed by Sano /Regeneron and marketed under the brand name Praluent, Evolocumab (AMG 145), developed by Amgen and marketed under the brand name Repatha as well as Bococizumab (RN316) developed by Pfizer and undergoing phase III clinical trials.

 

Alirocumab (Praluent)

 

Description

The first human monoclonal antibody against PCSK9 to be approved by the food and drug administration (FDA).

Indication

It is approved for use as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL-C.

Dosage

It is available in the form of a subcutaneous(sc) injection in the strength of 75 mg/ml as well as 150 mg/ml. The recommended starting dose is 75 mg every two weeks. If the LDL-C lowering response is inadequate, the dose may be increased to 150 mg every two weeks, which is also the maximum dose that can be administered.

 

Evolocumab (Repantha)

 

Description

The second drug approved by FDA under the class of PCSK9 inhibitors

Indication

Evolocumab (Repantha) is approved by FDA for the same indications as Alirocumab (Praluent). However, unlike Alirocumab (Praluent), Evolocumab (Repantha) is also indicated for homozygous familial hypercholesterolemia (HoFH) in addition to HeFH.

Dosage

It is available in the form of a sc injection in the strength of 140 mg/ml in a single use prefilled syringe as well as 420 mg/3.5ml in a single use Pushtronix system (on-body infusor with prefilled cartlidge). The recommended dose for HeFH is 140 mg every 2 weeks or 420 mg once a month while the recommended dose for HoFH is 420 mg once a month.

Dosage adjustment in renal or hepatic impairment

Both Alirocumab (Praluent) and Evolocumab (Repantha) do not require dosage adjustment in either mild to moderate renal or hepatic impairment. However, their safety in severe renal or hepatic impairment has not been studied yet.

Adverse effects

The most common side effects of both drugs include injection site reactions, such as itching, swelling, pain, or bruising, nasopharyngitis, upper respiratory tract infection, flu and back pain. Allergic reactions, such as rash and hives, have been reported. Patients should stop using these drugs and get medical help if they experience symptoms of a serious allergic reaction.

 

References   

 

 

SGLT2 inhibitors: New warnings!

By: Ph. Mohammad Al- Roomi      

 

Information on potential risk of toe amputation to be included in prescribing information

 

The European Medicines Agency (EMA) panel has determined that a warning stating that the sodium glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes may increase the risk for lower-limb amputation should be included in the prescribing information for all drugs in this class. Two clinical trials, CANVAS and CNAVAS-R, have been conducted and found this risk.

 

Information for healthcare professionals:

  • An increase in lower limb amputation (mostly affecting the toes) has been observed in two long-term clinical trials, CANVAS and CANVAS-R, in patients taking canagliflozin (Invokana,Vokanamet, Janssen)compared with those taking placebo. The studies, which are still ongoing, involved patients at high cardiovascular risk.
  • Although an increase in amputations has not been seen in studies with other SGLT2 inhibitors, dapagliflozin (Farxiga, XigduoXR, Ebymect, Edistride, Qtern, AstraZeneca) and empagliflozin (Jardiance, Glyxambi, Synjardy, BoehringerIngelheim), data available to date are limited and the risk may also apply to these other medicines.
  • The underlying mechanism by which canagliflozin may increase the risk of amputation has not been established and no risk factors apart from general risk factors for amputation have been identified.
  • As a precaution, patients taking an SGLT2-inhibitor should be counselled about the importance of routine preventative foot care.
  • For canagliflozin, consideration should also be given to carefully monitoring patients at higher risk of amputation and counselling them about the importance of maintaining adequate hydration.
  • Consideration may be given to stopping treatment with canagliflozin in patients who develop events preceding amputation such as lower-extremity skin ulcer, infection, osteomyelitis or gangrene.

 

Information for patients:

  • All patients with diabetes are at increased risk of infection and sores which can lead to amputations.
  • If you are taking medicines containing canagliflozin, dapagliflozin and empagliflozin to treat your type 2 diabetes, it is particularly important that you check your feet regularly and follow your doctor’s advice on routine preventative foot care and adequate hydration.
  • Tell your doctor about any wounds or discoloration, or if your feet are tender or painful.
  • If you have any questions or concerns about your treatment, speak to your doctor, pharmacist or nurse.

 

References:

Pharmacists around the world

By: Ph. Yasmeen Rafique

 

Pharmacists clinic

University of British Colombia

Faculty of pharmaceutical sciences (Vancouver, Canada)

 

The pharmacists clinic is where expert pharmacists work with patients and other health care professionals to optimize patient drug therapy outcomes. The clinic offers an effective way to care for patients with:

  • multiple drug therapies (polypharmacy)

    The pharmacists clinic at UBC
  • sub-optimal drug therapy outcomes
  • adverse drug events, drug sensitivities/allergies
  • a need to start or stop a drug therapy
  • patient adherence or compliance issues
  • questions about medications or other products
  • complex health conditions (e.g., diabetes, uncontrolled pain)
  • reduced liver or kidney function
  • advanced age (frailty)
  • recent discharge from hospital

 

The Pharmacists Clinic at UBC is the first of its kind in Canada. It offers a unique health care environment that integrates patient care with academic and research programs, working hand in hand with physicians and other members of the health care team to provide the most appropriate, effective and personalized drug therapy for patients. With the primary focus being the patient, it is important that the patient actively participates in the decision-making process regarding his/her treatment.

Patients need to make appointments prior to their visit. Appointments are available in person or by telephone. The first appointment is usually 60 minutes. Follow-up appointments are 30–60 minutes, depending on the patient’s needs. During the consultation, the patient is asked to provide a list of all prescription medications, non-prescription medications and natural health products that he/she is currently taking, all of which will be recorded to be analyzed to optimize the patient’s therapy. Physicians with a busy schedule can also refer patients to the pharmacists clinic to help them optimize their patients’ therapy. The physician will receive a detailed report of all the drug therapy recommendations as well as the follow-up plans for patients with referral. Patient referrals to the pharmacists clinic are processed within two business days. The services are provided at no cost to the physician or the patient. Services are funded in part by the ministry of health and in part by the faculty of pharmaceutical sciences.

Apart from optimizing drug therapy, the pharmacists at the clinic are also trained to vaccinate patients as well as monitor blood glucose levels and blood pressure.

 

Click to view video below:

Pharmacists clinic at UBC

 

Reference: https://pharmsci.ubc.ca/pharmacists-clinic

Drug development process

By: Ph. Mohammad Al Roomi

 

The drug development process is a set of thoroughly designed steps from the discovery of a lead compound to the end-market product that ensures the best safety and efficacy combination for each consumer and is regulated by the American Food and Drug Association (FDA). These steps are:

 

Step 1: Discovery and development

In this step the researchers discover new drugs through studying the disease process or test a new molecular compound and also review the previous treatment methods in order to minimize the amount of unwanted effects and better optimize the product. At this stage many compounds may be potential candidates for developing a new medical treatment.

After identifying a promising compound, experiments are conducted in order to gather more information about:

  • ADME (Absorption, Distribution, Metabolism, Excretion)
  • MOA (mechanism of action) and benefits
  • Optimal Dosage
  • Optimal Route of administration
  • Side-effects
  • The effect of different variables (Race, Gender, Ethnicity, etc..)

 

Step 2: Preclinical Research:

In this step the drugs mainly undergo laboratory and animal testing in order to get detailed information on dosing and toxicity levels. After preclinical testing, researchers review their findings and decide whether the drug should be tested on human subjects.

 

Step 3: Clinical Research or clinical trials:

Clinical Research or Clinical Trials is the first step which involves the participation of human subjects and the gathering of the drug or compound effect on the human body. However, before starting the clinical trials the developers must begin the Investigational New Drug Process (IND).  In this process an application is submitted to FDA which includes:

  • Animal study data and toxicity data
  • Manufacturing information.
  • Clinical protocols (study plans) for studies to be conducted.
  • Data from any prior human research.
  • Information about the investigator.

The submission of the application is followed by 30 days of study period to give either the approval for the next stage or the denial and termination of study, which is rare. This approval process gives protection to the human volunteers against any significant harm that may accompany this drug. After the approval is given, trials begin and are divided into three phases and if the treatment is successful in one phase it moves to the next phase. The first phase consists of a small number of healthy human volunteers or diseased volunteers of 20 to 100 subjects and this phase mainly takes several months. The drug safety and dosage will be thoroughly studied and 70% of drugs move on to the next phase. Phase two trials consist of hundreds of patients with a disease that the drug is intended to affect and will be studying the efficacy and side-effects of the drug and will take months to 2 years of study. Approximately 33% of drugs move on to the next stage, which is Phase three. The Final Phase is much larger and broader and consists of 300-3000 diseased volunteers and will also monitor the drug’s efficacy and side effects and this phase will take from 1 year to 4 years of research and study.

 

Step 4: FDA Review

If a drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file a New Drug Application (NDA) to market the drug. In the NDA, a drug developer must include everything about a drug—from preclinical data to Phase 3 trial data. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include:

  • Proposed labeling
  • Safety updates
  • Drug abuse information
  • Patent information
  • Any data from studies that may have been conducted outside the United States
  • Institutional review board compliance information
  • Directions for use

A thorough examination of the submitted data and analytics and a decision is given to the team of developers to approve or disapprove the drug marketing for the public.

 

Step 5: FDA Post-Market Safety Monitoring:

Even though clinical trials provide important information on a drug’s efficacy and safety, it is impossible to have complete information about the safety of a drug at the time of approval. Despite the rigorous steps in the process of drug development, limitations exist. Therefore, the true picture of a product’s safety actually evolves over the months and even years that make up a product’s lifetime in the marketplace. FDA reviews reports of problems with prescription and over-the-counter drugs, and can decide to add cautions to the dosage or usage information, as well as other measures for more serious issues.

 

Reference:

https://www.fda.gov/ForPatients/Approvals/Drugs/default.htm