Drug Information Centre- Pgimer

11/11/2024

What is Menke’s disease?

Menkes disease (MD) is a rare disease, affecting 1 in 300,000 people. It is also known as Menkes steely hair disease, or Kinky hair syndrome because of characteristic steely woolly hairs. MD is a lethal multisystemic disorder due to abnormal copper metabolism. MD is caused by mutations in the ATP7A gene on X chromosome. ATP7A gene code for a copper-transport protein involved in final processing of several copper-dependent enzymes. The defect results in a systemic copper
deficiency and dysfunction of copper-dependent enzymes involved in cellular functioning, collagen synthesis and neurotransmission. Classical MD is inherited as an X-linked recessive disorder and affect boys in early infancy.
Seizures, neurodegeneration, connective tissue disorder and Kinky hair are predominant manifestations of MD.

Symptoms in children with MD evolve with age:
o Cephalohematomas and spontaneous fractures at birth
o Prolonged jaundice, hypothermia, hypoglycaemia and feeding difficulties in
neonatal period.
o Unusual sparse and lustreless scalp hair that becomes tangled on the top of
the head at the age of 1–2 months
o Initial developmental milestone is normal up to about 2–4 months of age.
subsequently development becomes slow and stagnant.
o By 4-5 months most patients develop seizures, which are poorly controlled
with medications.
o Developmental regressions become obvious with seizure onset.
o Feeding difficulty leads to failure to thrive, poor swallowing leading to
vomiting, recurrent cough and aspiration pneumonia.
o Most affected patients are hypotonic in early life, later develop paucity of
spontaneous activity and develop spasticity.
o Boys affected with MD appears pale, lethargic, have frontal or occipital
bossing, micrognathia, pudgy cheeks, seborrheic dermatitis and a rather
expressionless appearance with woolly steely and kinky hairs.
o Cutis laxa, hernia, bony abnormalities are other features
o MRI brain shows brain atrophy and abnormally dilated and tortuous blood
vessels.

Diagnosis of MD require hair microscopy, EEG, MRI Brain, serum copper and ceruloplasmin levels and genetic testing for ATP7A gene

Outcome and survival: Severely affected children with MD die usually before the third
year of life.

Treatment: Supportive care, nutrition with feeding tube if needed, anti-seizure medications. Curative therapy for MD does not exist. Very early copper–histidine treatment initiation may improve some of the neurological symptoms. Copper histidine therapy is administered subcutaneously daily.

For more information related to copper histidine therapy availability in India, you may contact at PGIMER Drug information centre.

21/11/2023

Question : Where to get Yellow fever vaccination for person staying in any part of tricity ( chandigarh panchkula mohali)?
Answer : Mohali civil hospital and CRI Kasauli

26/03/2021

Question : Which is a safer anti fungal for mold prophylaxis in acute myeloid leukaemia pregnant patient with 26 weeks of gestation?

Answer : Liposomal amphotericin B intravenous infusion 7 mg/kg IV weekly. Administration should be over over 2 hours

Reference

Antifungal therapy guidelines department of clinical hematology Oxford university hospitals NHS

19/03/2020

09/12/2019

Que: By what all routes colistin can be administered to a gram-negative sepsis patient?

Ans: Colistin can be given by intraventricular [ i.e. direct injection in omaya reservoir/ shunt] [1], inhalational route when IV colistin alone is not helping much [2], and intrathecal when the excess fibrosis or excess porosity of BBB is creating hurdles.[3]

References:
1. Imberti R, Cusato M, Accetta G, et al. Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate. Antimicrob Agents Chemother. 2012;56(8):4416–4421. doi:10.1128/AAC.00231-12

2. Choi HK, Kim YK, Kim HY, Uh Y. Inhaled colistin for treatment of pneumonia due to colistin-only-susceptible Acinetobacter baumannii. Yonsei Med J. 2014;55(1):118–125. doi:10.3349/ymj.2014.55.1.118

3. Yagmur R, Esen F. Intrathecal colistin for treatment of Pseudomonas aeruginosa ventriculitis: report of a case with successful outcome. Crit Care. 2006;10(6):428. doi:10.1186/cc5088

25/11/2019

Que: What are the treatment options in colistin Hypersensitive patient when Antibiotic susceptibility Testing mentioning colistin sensitive organism?

Ans: Tigecycline can be used as mentioned in RCT's but meta-analysis questions role & refute the usefulness. Colistin based combination therapies are also an option since the AST does not take into account the synergistic action of two antimicrobials.

Reference:

Ni W, Li Y, Guan J, et al. Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria. Antimicrob Agents Chemother. 2016;60(5):3215–3218. Published 2016 Apr 22. doi:10.1128/AAC.00248-16

Sipahi OR, Mermer S, Demirdal T, Ulu AC, Fillatre P, Ozcem SB, Kaya Ş, Şener A, Bulut C, Tekin R, Kahraman H, Özgiray E, Yurtseven T, Sipahi H, Arda B, Pullukçu H, Taşbakan M, Yamazhan T, Aydemir S, Ulusoy S. Tigecycline in the
treatment of multidrug-resistant Acinetobacter baumannii meningitis: Results of the Ege study. Clin Neurol Neurosurg. 2018 Sep;172:31-38. doi: 10.1016/j.clineuro.2018.06.008. Epub 2018 Jun 10. PubMed PMID: 29960893.

Wang J, He JT, Bai Y, Wang R, Cai Y. Synergistic Activity of Colistin/Fosfomycin Combination against Carbapenemase-Producing Klebsiella pneumoniae in an In Vitro Pharmacokinetic/Pharmacodynamic Model. Biomed Res Int. 2018;2018:5720417. Published 2018 Apr 23. doi:10.1155/2018/5720417

17/10/2019

Oral Contraceptives and Reduced Lamotrigine Efficacy

In this unusual interaction, oral contraceptives act as the precipitant rather than the object drug.
For most reported drug interactions involving oral contraceptives (OCs), the OC is the drug affected by the interaction (ie, the “object drug”). For example, enzyme inducers such as rifampin enhance the metabolism of OCs, thus increasing the risk of contraceptive failure and unintended pregnancy.
Some data suggest that OCs can affect the metabolism of drugs metabolized by cytochrome P450 (CYP) 1A2 or CYP3A4 and possibly other enzymes, but the interactions are generally not considered of high clinical importance.1 The ability of OCs to reduce lamotrigine plasma concentrations and efficacy, however, is well documented and probably of substantial clinical importance.
What Data Support the Interaction?
Over a decade ago, a report described 7 patients who developed a mean 49% decrease in lamotrigine plasma concentrations with concurrent use of OCs.2 Some patients developed reduced seizure control following OC use.
In a later study by the same group, lamotrigine plasma concentrations were compared in 22 women taking lamotrigine with a combined OC (ethinyl estradiol plus a progestogen) and 30 women taking lamotrigine without OCs. The mean steady state lamotrigine concentration in those taking OCs was less than half that seen in the women not taking OCs.3
Several subsequent studies have confirmed that lamotrigine plasma concentrations are substantially lower in women taking combined OCs (ethinyl estradiol plus a progestogen) than in those not taking an OC.4-7 In most studies, women taking OCs have lamotrigine plasma concentrations approximately 40% to 50% lower than those not taking OCs. In one study, it took about 8 days after starting the OC for the maximal decrease in lamotrigine levels.
Although most of the studies of this interaction were short-term and involved relatively small numbers of patients (approximately 20 to 50), reductions in lamotrigine plasma concentrations have been consistently found. Moreover, the magnitude of the interaction is such that one should expect reduced lamotrigine efficacy with an increased risk of seizures in at least some patients.
The clinical evidence suggests that lamotrigine levels may increase during the “pillfree” week when the OC is temporarily discontinued.7 Accordingly, if lamotrigine dosage has been increased to compensate for the OC interaction, stopping the OC may result in lamotrigine adverse effects, as has been reported in some patients.2
What Is the Mechanism?
Lamotrigine clearance is substantially higher in patients taking OCs, probably due to the ability of the estrogenic component of the OC (ethinyl estradiol) to induce the hepatic glucuronidation of lamotrigine. Other evidence suggests that OCs can enhance glucuronidation of concurrently administered drugs.
Do Progestogen-Only OCs Interact?
Women receiving progestogen-only contraceptives (oral, topical, or parenteral) did not have lower lamotrigine serum concentrations in one study.4 The number of patients studied was small, however, so more research is needed to establish whether progestogen-only contraception interacts with lamotrigine.
Summary
There is convincing clinical evidence that combined OCs containing ethinyl estradiol can substantially reduce lamotrigine plasma concentrations, thus increasing the risk of seizures.
If OCs are added to lamotrigine therapy, it would be prudent to monitor lamotrigine plasma levels before and after starting the OC. Adjustments in lamotrigine dose may be necessary. One should also consider the possibility that a change in the estrogen content of an OC may result in changes in lamotrigine plasma concentrations.
Overall, it would appear that, with careful monitoring, one can safely combine lamotrigine and OCs, but in selected patients it may be preferable to avoid the combination.
Preliminary evidence suggests that, unlike ethinyl estradiol, progestogens do not interact with lamotrigine, so using progestogen-only contraception may prove to be a method of avoiding the interaction. Nonhormonal methods of contraception may also be used to avoid the interaction if necessary. PT
Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy.
References
1. Reddy DS. Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives. Expert Rev Clin Pharmacol. 2010;3:183-192.
2. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47:151-154.
3. Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology. 2003;61:570-571.
4. Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia. 2005;46:1414-1417.
5. Sidhu J, Job S, Singh S, Phillipson R. The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol. 2005;61:191-199.
6. Herzog AG, BlumAS, Farina EL, et al. Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use. Neurology. 2009;72:911-914.
7. Wegner I, Edelbroek PM, Bulk S, Lindhout D. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology. 2009;73:1388-1393.

26/09/2019

Polatuzumab

There is no consensus regarding the optimal treatment of diffuse large B cell lymphoma (DLBCL) that has relapsed following autologous hematopoietic cell transplantation (HCT). Polatuzumab vedotin is an anti-CD79b antibody-drug immunoconjugate that is active against B cell lymphomas. In a multicenter trial, among 80 patients with relapsed/refractory DLBCL, the addition of polatuzumab to bendamustine and rituximab (PBR) improved complete and overall response rates and resulted in a longer duration of remission. Polatuzumab is approved by the US Food and Drug Administration (FDA) for multiply relapsed DLBCL, and prescribing information includes warnings for peripheral neuropathy, progressive multifocal leukoencephalopathy (PML), tumor lysis syndrome, and fetal toxicity. We consider PBR as an acceptable alternative to chimeric antigen receptor T cell therapy (CAR-T), allogeneic HCT, and other approaches for multiply relapsed DLBCL

Reference:

www.uptodate.com

25/09/2019

Selinexor plus dexamethasone

There are few treatments for penta-refractory multiple myeloma (MM), defined as MM refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody. In a phase II trial enrolling patients with heavily pretreated MM, dexamethasone plus the first-in-class oral nuclear export inhibitor selinexor led to responses in approximately 25 percent, with a median duration of response of 4.4 months. This led to US Food and Drug Administration approval of selinexor plus dexamethasone for penta-refractory MM. Given the significant toxicities, patients taking this combination should receive antiemetic prophylaxis, avoid other medications that cause dizziness or confusion, and be monitored for thrombocytopenia, neutropenia, and hyponatremia. As we await more data from randomized trials, we reserve selinexor as a last resort in select patients willing to accept the known toxicity and uncertain benefit.

Reference:

www.uptodate.com

24/09/2019

Fedratinib

There are limited treatment options for symptom relief in patients with higher-risk myelofibrosis (MF) who are not eligible for allogeneic hematopoietic cell transplantation (HCT). In a randomized trial comparing the JAK2-selective kinase inhibitor fedratinib with placebo in higher-risk MF patients, over one-third receiving fedratinib had decreased splenomegaly and improved MF symptoms. Fedratinib was approved by the US Food and Drug Administration for treatment of MF, with a warning regarding possible serious or fatal Wernicke-like encephalopathy. Serum thiamine should be measured before and periodically during therapy and, if signs of encephalopathy develop, fedratinib should be discontinued immediately and parenteral thiamine is given. We consider fedratinib an acceptable alternative to ruxolitinib or hydroxyurea for relief of MF-associated symptoms in patients who are not eligible for allogeneic HCT.

Reference:
http://www.uptodate.com

23/09/2019

Risankizumab versus adalimumab for moderate to severe plaque psoriasi

Clinical trials that compare new therapies for psoriasis to older therapies, such as the anti-tumor necrosis factor agent adalimumab, are useful for guiding treatment selection. In a phase 3 randomized trial, risankizumab (a newer anti-IL-23 drug) was more effective than adalimumab for moderate to severe plaque psoriasis. In addition, patients who switched to risankizumab after an intermediate response to adalimumab were more likely to achieve significant clinical improvement than patients who continued adalimumab. Adverse effect rates for risankizumab and adalimumab were similar. The findings of this trial support risankizumab for plaque psoriasis both as an initial therapy as well as a subsequent treatment for patients who have had an unsatisfactory response to adalimumab.

Reference:
http://www.uptodate.com

04/09/2019

Que: What should be done in the treatment of invasive Aspergillosis if the Voriconazole levels show a concentration of 18 micrograms per ml?

Ans: Azoles stands as drug of choice for aspergillosis. Voriconazole concentration is definitely in the toxic range. Stop voriconazole for one and half-day [ 5 half lives] and restart the patient on the lower doses i.e. 200 mg BD and titrate dosing accordingly. Adding Amphotericin B is not recommended in the presence of Azoles.

Reference:
https://www.idsociety.org/globalassets/idsa/practice-guidelines/practice-guidelines-for-the-diagnosis-and-management-of-aspergillosis-2016-update-by-the-infectious-diseases-society-of-america.pdf

Chen K, Zhang X, Ke X, Du G, Yang K, Zhai S. Individualized Medication of Voriconazole: A Practice Guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. Ther Drug Monit. 2018;40(6):663–674. doi:10.1097/FTD.0000000000000561

Jenks JD, Hoenigl M. Treatment of Aspergillosis. J Fungi (Basel). 2018;4(3):98. Published 2018 Aug 19. doi:10.3390/jof4030098

Evidence Level: 2